Beate St Pourcain

Publications

Displaying 1 - 98 of 98
  • Cuellar-Partida, G., Tung, J. Y., Eriksson, N., Albrecht, E., Aliev, F., Andreassen, O. A., Barroso, I., Beckmann, J. S., Boks, M. P., Boomsma, D. I., Boyd, H. A., Breteler, M. M. B., Campbell, H., Chasman, D. I., Cherkas, L. F., Davies, G., De Geus, E. J. C., Deary, I. J., Deloukas, P., Dick, D. M. and 98 moreCuellar-Partida, G., Tung, J. Y., Eriksson, N., Albrecht, E., Aliev, F., Andreassen, O. A., Barroso, I., Beckmann, J. S., Boks, M. P., Boomsma, D. I., Boyd, H. A., Breteler, M. M. B., Campbell, H., Chasman, D. I., Cherkas, L. F., Davies, G., De Geus, E. J. C., Deary, I. J., Deloukas, P., Dick, D. M., Duffy, D. L., Eriksson, J. G., Esko, T., Feenstra, B., Geller, F., Gieger, C., Giegling, I., Gordon, S. D., Han, J., Hansen, T. F., Hartmann, A. M., Hayward, C., Heikkilä, K., Hicks, A. A., Hirschhorn, J. N., Hottenga, J.-J., Huffman, J. E., Hwang, L.-D., Ikram, M. A., Kaprio, J., Kemp, J. P., Khaw, K.-T., Klopp, N., Konte, B., Kutalik, Z., Lahti, J., Li, X., Loos, R. J. F., Luciano, M., Magnusson, S. H., Mangino, M., Marques-Vidal, P., Martin, N. G., McArdle, W. L., McCarthy, M. I., Medina-Gomez, C., Melbye, M., Melville, S. A., Metspalu, A., Milani, L., Mooser, V., Nelis, M., Nyholt, D. R., O'Connell, K. S., Ophoff, R. A., Palmer, C., Palotie, A., Palviainen, T., Pare, G., Paternoster, L., Peltonen, L., Penninx, B. W. J. H., Polasek, O., Pramstaller, P. P., Prokopenko, I., Raikkonen, K., Ripatti, S., Rivadeneira, F., Rudan, I., Rujescu, D., Smit, J. H., Smith, G. D., Smoller, J. W., Soranzo, N., Spector, T. D., St Pourcain, B., Starr, J. M., Stefánsson, H., Steinberg, S., Teder-Laving, M., Thorleifsson, G., Stefansson, K., Timpson, N. J., Uitterlinden, A. G., Van Duijn, C. M., Van Rooij, F. J. A., Vink, J. M., Vollenweider, P., Vuoksimaa, E., Waeber, G., Wareham, N. J., Warrington, N., Waterworth, D., Werge, T., Wichmann, H.-E., Widen, E., Willemsen, G., Wright, A. F., Wright, M. J., Xu, M., Zhao, J. H., Kraft, P., Hinds, D. A., Lindgren, C. M., Magi, R., Neale, B. M., Evans, D. M., & Medland, S. E. (2021). Genome-wide association study identifies 48 common genetic variants associated with handedness. Nature Human Behaviour, 5, 59-70. doi:10.1038/s41562-020-00956-y.

    Abstract

    Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10−8) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (rG = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.

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  • Verhoef, E., Shapland, C. Y., Fisher, S. E., Dale, P. S., & St Pourcain, B. (2021). The developmental genetic architecture of vocabulary skills during the first three years of life: Capturing emerging associations with later-life reading and cognition. PLoS Genetics, 17(2): e1009144. doi:10.1371/journal.pgen.1009144.

    Abstract

    Individual differences in early-life vocabulary measures are heritable and associated with subsequent reading and cognitive abilities, although the underlying mechanisms are little understood. Here, we (i) investigate the developmental genetic architecture of expressive and receptive vocabulary in early-life and (ii) assess timing of emerging genetic associations with mid-childhood verbal and non-verbal skills. We studied longitudinally assessed early-life vocabulary measures (15–38 months) and later-life verbal and non-verbal skills (7–8 years) in up to 6,524 unrelated children from the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. We dissected the phenotypic variance of rank-transformed scores into genetic and residual components by fitting multivariate structural equation models to genome-wide genetic-relationship matrices. Our findings show that the genetic architecture of early-life vocabulary involves multiple distinct genetic factors. Two of these genetic factors are developmentally stable and also contribute to genetic variation in mid-childhood skills: One genetic factor emerging with expressive vocabulary at 24 months (path coefficient: 0.32(SE = 0.06)) was also related to later-life reading (path coefficient: 0.25(SE = 0.12)) and verbal intelligence (path coefficient: 0.42(SE = 0.13)), explaining up to 17.9% of the phenotypic variation. A second, independent genetic factor emerging with receptive vocabulary at 38 months (path coefficient: 0.15(SE = 0.07)), was more generally linked to verbal and non-verbal cognitive abilities in mid-childhood (reading path coefficient: 0.57(SE = 0.07); verbal intelligence path coefficient: 0.60(0.10); performance intelligence path coefficient: 0.50(SE = 0.08)), accounting for up to 36.1% of the phenotypic variation and the majority of genetic variance in these later-life traits (≥66.4%). Thus, the genetic foundations of mid-childhood reading and cognitive abilities are diverse. They involve at least two independent genetic factors that emerge at different developmental stages during early language development and may implicate differences in cognitive processes that are already detectable during toddlerhood.

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  • Gialluisi, A., Andlauer, T. F. M., Mirza-Schreiber, N., Moll, K., Becker, J., Hoffmann, P., Ludwig, K. U., Czamara, D., St Pourcain, B., Honbolygó, F., Tóth, D., Csépe, V., Huguet, H., Chaix, Y., Iannuzzi, S., Demonet, J.-F., Morris, A. P., Hulslander, J., Willcutt, E. G., DeFries, J. C. and 29 moreGialluisi, A., Andlauer, T. F. M., Mirza-Schreiber, N., Moll, K., Becker, J., Hoffmann, P., Ludwig, K. U., Czamara, D., St Pourcain, B., Honbolygó, F., Tóth, D., Csépe, V., Huguet, H., Chaix, Y., Iannuzzi, S., Demonet, J.-F., Morris, A. P., Hulslander, J., Willcutt, E. G., DeFries, J. C., Olson, R. K., Smith, S. D., Pennington, B. F., Vaessen, A., Maurer, U., Lyytinen, H., Peyrard-Janvid, M., Leppänen, P. H. T., Brandeis, D., Bonte, M., Stein, J. F., Talcott, J. B., Fauchereau, F., Wilcke, A., Kirsten, H., Müller, B., Francks, C., Bourgeron, T., Monaco, A. P., Ramus, F., Landerl, K., Kere, J., Scerri, T. S., Paracchini, S., Fisher, S. E., Schumacher, J., Nöthen, M. M., Müller-Myhsok, B., & Schulte-Körne, G. (2020). Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia. Molecular Psychiatry. Advance online publication. doi:10.1038/s41380-020-00898-x.

    Abstract

    Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40–60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p  < 2.8 × 10−6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20–25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p  = 8 × 10−13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10−43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10−22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10−12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10−4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10−7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10−29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.
  • Grasby, K. L., Jahanshad, N., Painter, J. N., Colodro-Conde, L., Bralten, J., Hibar, D. P., Lind, P. A., Pizzagalli, F., Ching, C. R. K., McMahon, M. A. B., Shatokhina, N., Zsembik, L. C. P., Thomopoulos, S. I., Zhu, A. H., Strike, L. T., Agartz, I., Alhusaini, S., Almeida, M. A. A., Alnæs, D., Amlien, I. K. and 341 moreGrasby, K. L., Jahanshad, N., Painter, J. N., Colodro-Conde, L., Bralten, J., Hibar, D. P., Lind, P. A., Pizzagalli, F., Ching, C. R. K., McMahon, M. A. B., Shatokhina, N., Zsembik, L. C. P., Thomopoulos, S. I., Zhu, A. H., Strike, L. T., Agartz, I., Alhusaini, S., Almeida, M. A. A., Alnæs, D., Amlien, I. K., Andersson, M., Ard, T., Armstrong, N. J., Ashley-Koch, A., Atkins, J. R., Bernard, M., Brouwer, R. M., Buimer, E. E. L., Bülow, R., Bürger, C., Cannon, D. M., Chakravarty, M., Chen, Q., Cheung, J. W., Couvy-Duchesne, B., Dale, A. M., Dalvie, S., De Araujo, T. K., De Zubicaray, G. I., De Zwarte, S. M. C., Den Braber, A., Doan, N. T., Dohm, K., Ehrlich, S., Engelbrecht, H.-R., Erk, S., Fan, C. C., Fedko, I. O., Foley, S. F., Ford, J. M., Fukunaga, M., Garrett, M. E., Ge, T., Giddaluru, S., Goldman, A. L., Green, M. J., Groenewold, N. A., Grotegerd, D., Gurholt, T. P., Gutman, B. A., Hansell, N. K., Harris, M. A., Harrison, M. B., Haswell, C. C., Hauser, M., Herms, S., Heslenfeld, D. J., Ho, N. F., Hoehn, D., Hoffmann, P., Holleran, L., Hoogman, M., Hottenga, J.-J., Ikeda, M., Janowitz, D., Jansen, I. E., Jia, T., Jockwitz, C., Kanai, R., Karama, S., Kasperaviciute, D., Kaufmann, T., Kelly, S., Kikuchi, M., Klein, M., Knapp, M., Knodt, A. R., Krämer, B., Lam, M., Lancaster, T. M., Lee, P. H., Lett, T. A., Lewis, L. B., Lopes-Cendes, I., Luciano, M., Macciardi, F., Marquand, A. F., Mathias, S. R., Melzer, T. R., Milaneschi, Y., Mirza-Schreiber, N., Moreira, J. C. V., Mühleisen, T. W., Müller-Myhsok, B., Najt, P., Nakahara, S., Nho, K., Olde Loohuis, L. M., Orfanos, D. P., Pearson, J. F., Pitcher, T. L., Pütz, B., Quidé, Y., Ragothaman, A., Rashid, F. M., Reay, W. R., Redlich, R., Reinbold, C. S., Repple, J., Richard, G., Riedel, B. C., Risacher, S. L., Rocha, C. S., Mota, N. R., Salminen, L., Saremi, A., Saykin, A. J., Schlag, F., Schmaal, L., Schofield, P. R., Secolin, R., Shapland, C. Y., Shen, L., Shin, J., Shumskaya, E., Sønderby, I. E., Sprooten, E., Tansey, K. E., Teumer, A., Thalamuthu, A., Tordesillas-Gutiérrez, D., Turner, J. A., Uhlmann, A., Vallerga, C. L., Van der Meer, D., Van Donkelaar, M. M. J., Van Eijk, L., Van Erp, T. G. M., Van Haren, N. E. M., Van Rooij, D., Van Tol, M.-J., Veldink, J. H., Verhoef, E., Walton, E., Wang, M., Wang, Y., Wardlaw, J. M., Wen, W., Westlye, L. T., Whelan, C. D., Witt, S. H., Wittfeld, K., Wolf, C., Wolfers, T., Wu, J. Q., Yasuda, C. L., Zaremba, D., Zhang, Z., Zwiers, M. P., Artiges, E., Assareh, A. A., Ayesa-Arriola, R., Belger, A., Brandt, C. L., Brown, G. G., Cichon, S., Curran, J. E., Davies, G. E., Degenhardt, F., Dennis, M. F., Dietsche, B., Djurovic, S., Doherty, C. P., Espiritu, R., Garijo, D., Gil, Y., Gowland, P. A., Green, R. C., Häusler, A. N., Heindel, W., Ho, B.-C., Hoffmann, W. U., Holsboer, F., Homuth, G., Hosten, N., Jack Jr., C. R., Jang, M., Jansen, A., Kimbrel, N. A., Kolskår, K., Koops, S., Krug, A., Lim, K. O., Luykx, J. J., Mathalon, D. H., Mather, K. A., Mattay, V. S., Matthews, S., Mayoral Van Son, J., McEwen, S. C., Melle, I., Morris, D. W., Mueller, B. A., Nauck, M., Nordvik, J. E., Nöthen, M. M., O’Leary, D. S., Opel, N., Paillère Martinot, M.-L., Pike, G. B., Preda, A., Quinlan, E. B., Rasser, P. E., Ratnakar, V., Reppermund, S., Steen, V. M., Tooney, P. A., Torres, F. R., Veltman, D. J., Voyvodic, J. T., Whelan, R., White, T., Yamamori, H., Adams, H. H. H., Bis, J. C., Debette, S., Decarli, C., Fornage, M., Gudnason, V., Hofer, E., Ikram, M. A., Launer, L., Longstreth, W. T., Lopez, O. L., Mazoyer, B., Mosley, T. H., Roshchupkin, G. V., Satizabal, C. L., Schmidt, R., Seshadri, S., Yang, Q., Alzheimer’s Disease Neuroimaging Initiative, CHARGE Consortium, EPIGEN Consortium, IMAGEN Consortium, SYS Consortium, Parkinson’s Progression Markers Initiative, Alvim, M. K. M., Ames, D., Anderson, T. J., Andreassen, O. A., Arias-Vasquez, A., Bastin, M. E., Baune, B. T., Beckham, J. C., Blangero, J., Boomsma, D. I., Brodaty, H., Brunner, H. G., Buckner, R. L., Buitelaar, J. K., Bustillo, J. R., Cahn, W., Cairns, M. J., Calhoun, V., Carr, V. J., Caseras, X., Caspers, S., Cavalleri, G. L., Cendes, F., Corvin, A., Crespo-Facorro, B., Dalrymple-Alford, J. C., Dannlowski, U., De Geus, E. J. C., Deary, I. J., Delanty, N., Depondt, C., Desrivières, S., Donohoe, G., Espeseth, T., Fernández, G., Fisher, S. E., Flor, H., Forstner, A. J., Francks, C., Franke, B., Glahn, D. C., Gollub, R. L., Grabe, H. J., Gruber, O., Håberg, A. K., Hariri, A. R., Hartman, C. A., Hashimoto, R., Heinz, A., Henskens, F. A., Hillegers, M. H. J., Hoekstra, P. J., Holmes, A. J., Hong, L. E., Hopkins, W. D., Hulshoff Pol, H. E., Jernigan, T. L., Jönsson, E. G., Kahn, R. S., Kennedy, M. A., Kircher, T. T. J., Kochunov, P., Kwok, J. B. J., Le Hellard, S., Loughland, C. M., Martin, N. G., Martinot, J.-L., McDonald, C., McMahon, K. L., Meyer-Lindenberg, A., Michie, P. T., Morey, R. A., Mowry, B., Nyberg, L., Oosterlaan, J., Ophoff, R. A., Pantelis, C., Paus, T., Pausova, Z., Penninx, B. W. J. H., Polderman, T. J. C., Posthuma, D., Rietschel, M., Roffman, J. L., Rowland, L. M., Sachdev, P. S., Sämann, P. G., Schall, U., Schumann, G., Scott, R. J., Sim, K., Sisodiya, S. M., Smoller, J. W., Sommer, I. E., St Pourcain, B., Stein, D. J., Toga, A. W., Trollor, J. N., Van der Wee, N. J. A., van 't Ent, D., Völzke, H., Walter, H., Weber, B., Weinberger, D. R., Wright, M. J., Zhou, J., Stein, J. L., Thompson, P. M., & Medland, S. E. (2020). The genetic architecture of the human cerebral cortex. Science, 367(6484): eaay6690. doi:10.1126/science.aay6690.

    Abstract

    The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson’s disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
  • Howe, L. J., Hemani, G., Lesseur, C., Gaborieau, V., Ludwig, K. U., Mangold, E., Brennan, P., Ness, A. R., St Pourcain, B., Smith, G. D., & Lewis, S. J. (2020). Evaluating shared genetic influences on nonsyndromic cleft lip/palate and oropharyngeal neoplasms. Genetic Epidemiology, 44(8), 924-933. doi:10.1002/gepi.22343.

    Abstract

    It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g.,CDH1,AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13;p = .000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10;p = .55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.

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    Supporting information
  • Verhoef, E., Shapland, C. Y., Fisher, S. E., Dale, P. S., & St Pourcain, B. (2020). The developmental origins of genetic factors influencing language and literacy: Associations with early-childhood vocabulary. Journal of Child Psychology and Psychiatry. Advance online publication. doi:10.1111/jcpp.13327.

    Abstract

    Background The heritability of language and literacy skills increases from early‐childhood to adolescence. The underlying mechanisms are little understood and may involve (a) the amplification of genetic influences contributing to early language abilities, and/or (b) the emergence of novel genetic factors (innovation). Here, we investigate the developmental origins of genetic factors influencing mid‐childhood/early‐adolescent language and literacy. We evaluate evidence for the amplification of early‐childhood genetic factors for vocabulary, in addition to genetic innovation processes. Methods Expressive and receptive vocabulary scores at 38 months, thirteen language‐ and literacy‐related abilities and nonverbal cognition (7–13 years) were assessed in unrelated children from the Avon Longitudinal Study of Parents and Children (ALSPAC, Nindividuals ≤ 6,092). We investigated the multivariate genetic architecture underlying early‐childhood expressive and receptive vocabulary, and each of 14 mid‐childhood/early‐adolescent language, literacy or cognitive skills with trivariate structural equation (Cholesky) models as captured by genome‐wide genetic relationship matrices. The individual path coefficients of the resulting structural models were finally meta‐analysed to evaluate evidence for overarching patterns. Results We observed little support for the emergence of novel genetic sources for language, literacy or cognitive abilities during mid‐childhood or early adolescence. Instead, genetic factors of early‐childhood vocabulary, especially those unique to receptive skills, were amplified and represented the majority of genetic variance underlying many of these later complex skills (≤99%). The most predictive early genetic factor accounted for 29.4%(SE = 12.9%) to 45.1%(SE = 7.6%) of the phenotypic variation in verbal intelligence and literacy skills, but also for 25.7%(SE = 6.4%) in performance intelligence, while explaining only a fraction of the phenotypic variation in receptive vocabulary (3.9%(SE = 1.8%)). Conclusions Genetic factors contributing to many complex skills during mid‐childhood and early adolescence, including literacy, verbal cognition and nonverbal cognition, originate developmentally in early‐childhood and are captured by receptive vocabulary. This suggests developmental genetic stability and overarching aetiological mechanisms.

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    supporting information
  • Demontis, D., Walters, R. K., Martin, J., Mattheisen, M., Als, T. D., Agerbo, E., Baldursson, G., Belliveau, R., Bybjerg-Grauholm, J., Bækvad-Hansen, M., Cerrato, F., Chambert, K., Churchhouse, C., Dumont, A., Eriksson, N., Gandal, M., Goldstein, J. I., Grasby, K. L., Grove, J., Gudmundsson, O. O. and 61 moreDemontis, D., Walters, R. K., Martin, J., Mattheisen, M., Als, T. D., Agerbo, E., Baldursson, G., Belliveau, R., Bybjerg-Grauholm, J., Bækvad-Hansen, M., Cerrato, F., Chambert, K., Churchhouse, C., Dumont, A., Eriksson, N., Gandal, M., Goldstein, J. I., Grasby, K. L., Grove, J., Gudmundsson, O. O., Hansen, C. S., Hauberg, M. E., Hollegaard, M. V., Howrigan, D. P., Huang, H., Maller, J. B., Martin, A. R., Martin, N. G., Moran, J., Pallesen, J., Palmer, D. S., Pedersen, C. B., Pedersen, M. G., Poterba, T., Poulsen, J. B., Ripke, S., Robinson, E. B., Satterstrom, F. K., Stefansson, H., Stevens, C., Turley, P., Walters, G. B., Won, H., Wright, M. J., ADHD Working Group of the Psychiatric Genomics Consortium (PGC), EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium, 23andme Research Team, Andreassen, O. A., Asherson, P., Burton, C. L., Boomsma, D. I., Cormand, B., Dalsgaard, S., Franke, B., Gelernter, J., Geschwind, D., Hakonarson, H., Haavik, J., Kranzler, H. R., Kuntsi, J., Langley, K., Lesch, K.-P., Middeldorp, C., Reif, A., Rohde, L. A., Roussos, P., Schachar, R., Sklar, P., Sonuga-Barke, E. J. S., Sullivan, P. F., Thapar, A., Tung, J. Y., Waldman, I. D., Medland, S. E., Stefansson, K., Nordentoft, M., Hougaard, D. M., Werge, T., Mors, O., Mortensen, P. B., Daly, M. J., Faraone, S. V., Børglum, A. D., & Neale, B. (2019). Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature Genetics, 51, 63-75. doi:10.1038/s41588-018-0269-7.

    Abstract

    Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
  • Gialluisi, A., Andlauer, T. F. M., Mirza-Schreiber, N., Moll, K., Becker, J., Hoffmann, P., Ludwig, K. U., Czamara, D., St Pourcain, B., Brandler, W., Honbolygó, F., Tóth, D., Csépe, V., Huguet, G., Morris, A. P., Hulslander, J., Willcutt, E. G., DeFries, J. C., Olson, R. K., Smith, S. D. and 25 moreGialluisi, A., Andlauer, T. F. M., Mirza-Schreiber, N., Moll, K., Becker, J., Hoffmann, P., Ludwig, K. U., Czamara, D., St Pourcain, B., Brandler, W., Honbolygó, F., Tóth, D., Csépe, V., Huguet, G., Morris, A. P., Hulslander, J., Willcutt, E. G., DeFries, J. C., Olson, R. K., Smith, S. D., Pennington, B. F., Vaessen, A., Maurer, U., Lyytinen, H., Peyrard-Janvid, M., Leppänen, P. H. T., Brandeis, D., Bonte, M., Stein, J. F., Talcott, J. B., Fauchereau, F., Wilcke, A., Francks, C., Bourgeron, T., Monaco, A. P., Ramus, F., Landerl, K., Kere, J., Scerri, T. S., Paracchini, S., Fisher, S. E., Schumacher, J., Nöthen, M. M., Müller-Myhsok, B., & Schulte-Körne, G. (2019). Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia. Translational Psychiatry, 9(1): 77. doi:10.1038/s41398-019-0402-0.

    Abstract

    Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562–3468). We observed a genome-wide significant effect (p < 1 × 10−8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10−9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10−8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10−8) and with all the cognitive traits tested (p = 3.07 × 10−8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10−5–10−7]) and negatively associated with ADHD PRS (p ~ [10−8−10−17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.
  • Grove, J., Ripke, S., Als, T. D., Mattheisen, M., Walters, R., Won, H., Pallesen, J., Agerbo, E., Andreassen, O. A., Anney, R., Belliveau, R., Bettella, F., Buxbaum, J. D., Bybjerg-Grauholm, J., Bækved-Hansen, M., Cerrato, F., Chambert, K., Christensen, J. H., Churchhouse, C., Dellenvall, K. and 55 moreGrove, J., Ripke, S., Als, T. D., Mattheisen, M., Walters, R., Won, H., Pallesen, J., Agerbo, E., Andreassen, O. A., Anney, R., Belliveau, R., Bettella, F., Buxbaum, J. D., Bybjerg-Grauholm, J., Bækved-Hansen, M., Cerrato, F., Chambert, K., Christensen, J. H., Churchhouse, C., Dellenvall, K., Demontis, D., De Rubeis, S., Devlin, B., Djurovic, S., Dumont, A., Goldstein, J., Hansen, C. S., Hauberg, M. E., Hollegaard, M. V., Hope, S., Howrigan, D. P., Huang, H., Hultman, C., Klei, L., Maller, J., Martin, J., Martin, A. R., Moran, J., Nyegaard, M., Nærland, T., Palmer, D. S., Palotie, A., Pedersen, C. B., Pedersen, M. G., Poterba, T., Poulsen, J. B., St Pourcain, B., Qvist, P., Rehnström, K., Reichenberg, A., Reichert, J., Robinson, E. B., Roeder, K., Roussos, P., Saemundsen, E., Sandin, S., Satterstrom, F. K., Smith, G. D., Stefansson, H., Stefansson, K., Steinberg, S., Stevens, C., Sullivan, P. F., Turley, P., Walters, G. B., Xu, X., Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Me Research Team, Geschwind, D., Nordentoft, M., Hougaard, D. M., Werge, T., Mors, O., Mortensen, P. B., Neale, B. M., Daly, M. J., & Børglum, A. D. (2019). Identification of common genetic risk variants for autism spectrum disorder. Nature Genetics, 51, 431-444. doi:10.1038/s41588-019-0344-8.

    Abstract

    Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

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  • Gunz, P., Tilot, A. K., Wittfeld, K., Teumer, A., Shapland, C. Y., Van Erp, T. G. M., Dannemann, M., Vernot, B., Neubauer, S., Guadalupe, T., Fernandez, G., Brunner, H., Enard, W., Fallon, J., Hosten, N., Völker, U., Profico, A., Di Vincenzo, F., Manzi, G., Kelso, J. and 7 moreGunz, P., Tilot, A. K., Wittfeld, K., Teumer, A., Shapland, C. Y., Van Erp, T. G. M., Dannemann, M., Vernot, B., Neubauer, S., Guadalupe, T., Fernandez, G., Brunner, H., Enard, W., Fallon, J., Hosten, N., Völker, U., Profico, A., Di Vincenzo, F., Manzi, G., Kelso, J., St Pourcain, B., Hublin, J.-J., Franke, B., Pääbo, S., Macciardi, F., Grabe, H. J., & Fisher, S. E. (2019). Neandertal introgression sheds light on modern human endocranial globularity. Current Biology, 29(1), 120-127. doi:10.1016/j.cub.2018.10.065.

    Abstract

    One of the features that distinguishes modern humans from our extinct relatives and ancestors is a globular shape of the braincase [1-4]. As the endocranium closely mirrors the outer shape of the brain, these differences might reflect altered neural architecture [4,5]. However, in the absence of fossil brain tissue the underlying neuroanatomical changes as well as their genetic bases remain elusive. To better understand the biological foundations of modern human endocranial shape, we turn to our closest extinct relatives, the Neandertals. Interbreeding between modern humans and Neandertals has resulted in introgressed fragments of Neandertal DNA in the genomes of present-day non- Africans [6,7]. Based on shape analyses of fossil skull endocasts, we derive a measure of endocranial globularity from structural magnetic resonance imaging (MRI) scans of thousands of modern humans, and study the effects of introgressed fragments of Neandertal DNA on this phenotype. We find that Neandertal alleles on chromosomes 1 and 18 are associated with reduced endocranial globularity. These alleles influence expression of two nearby genes, UBR4 and PHLPP1, which are involved in neurogenesis and myelination, respectively. Our findings show how integration of fossil skull data with archaic genomics and neuroimaging can suggest developmental mechanisms that may contribute to the unique modern human endocranial shape.

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  • Haworth, S., Shapland, C. Y., Hayward, C., Prins, B. P., Felix, J. F., Medina-Gomez, C., Rivadeneira, F., Wang, C., Ahluwalia, T. S., Vrijheid, M., Guxens, M., Sunyer, J., Tachmazidou, I., Walter, K., Iotchkova, V., Jackson, A., Cleal, L., Huffmann, J., Min, J. L., Sass, L. and 15 moreHaworth, S., Shapland, C. Y., Hayward, C., Prins, B. P., Felix, J. F., Medina-Gomez, C., Rivadeneira, F., Wang, C., Ahluwalia, T. S., Vrijheid, M., Guxens, M., Sunyer, J., Tachmazidou, I., Walter, K., Iotchkova, V., Jackson, A., Cleal, L., Huffmann, J., Min, J. L., Sass, L., Timmers, P. R. H. J., UK10K consortium, Davey Smith, G., Fisher, S. E., Wilson, J. F., Cole, T. J., Fernandez-Orth, D., Bønnelykke, K., Bisgaard, H., Pennell, C. E., Jaddoe, V. W. V., Dedoussis, G., Timpson, N. J., Zeggini, E., Vitart, V., & St Pourcain, B. (2019). Low-frequency variation in TP53 has large effects on head circumference and intracranial volume. Nature Communications, 10: 357. doi:10.1038/s41467-018-07863-x.

    Abstract

    Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences affecting these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic influences and low-frequency genetic variation. To understand these influences, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV+HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.

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    Supplementary Information
  • Howe, L. J., Richardson, T. G., Arathimos, R., Alvizi, L., Passos-Bueno, M. R., Stanier, P., Nohr, E., Ludwig, K. U., Mangold, E., Knapp, M., Stergiakouli, E., St Pourcain, B., Smith, G. D., Sandy, J., Relton, C. L., Lewis, S. J., Hemani, G., & Sharp, G. C. (2019). Evidence for DNA methylation mediating genetic liability to non-syndromic cleft lip/palate. Epigenomics, 11(2), 133-145. doi:10.2217/epi-2018-0091.

    Abstract

    Aim: To determine if nonsyndromic cleft lip with or without cleft palate (nsCL/P) genetic risk variants influence liability to nsCL/P through gene regulation pathways, such as those involving DNA methylation. Materials & methods: nsCL/P genetic summary data and methylation data from four studies were used in conjunction with Mendelian randomization and joint likelihood mapping to investigate potential mediation of nsCL/P genetic variants. Results & conclusion: Evidence was found at VAX1 (10q25.3), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant, suggesting that genetic variation at these loci may increase liability to nsCL/P by influencing DNA methylation. Follow-up analyses using different tissues and gene expression data provided further insight into possible biological mechanisms.

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    Supplementary material
  • Howe, L., Lawson, D. J., Davies, N. M., St Pourcain, B., Lewis, S. J., Smith, G. D., & Hemani, G. (2019). Genetic evidence for assortative mating on alcohol consumption in the UK Biobank. Nature Communications, 10: 5039. doi:10.1038/s41467-019-12424-x.

    Abstract

    Alcohol use is correlated within spouse-pairs, but it is difficult to disentangle effects of alcohol consumption on mate-selection from social factors or the shared spousal environment. We hypothesised that genetic variants related to alcohol consumption may, via their effect on alcohol behaviour, influence mate selection. Here, we find strong evidence that an individual’s self-reported alcohol consumption and their genotype at rs1229984, a missense variant in ADH1B, are associated with their partner’s self-reported alcohol use. Applying Mendelian randomization, we estimate that a unit increase in an individual’s weekly alcohol consumption increases partner’s alcohol consumption by 0.26 units (95% C.I. 0.15, 0.38; P = 8.20 × 10−6). Furthermore, we find evidence of spousal genotypic concordance for rs1229984, suggesting that spousal concordance for alcohol consumption existed prior to cohabitation. Although the SNP is strongly associated with ancestry, our results suggest some concordance independent of population stratification. Our findings suggest that alcohol behaviour directly influences mate selection.
  • Linnér, R. K., Biroli, P., Kong, E., Meddens, S. F. W., Wedow, R., Fontana, M. A., Lebreton, M., Tino, S. P., Abdellaoui, A., Hammerschlag, A. R., Nivard, M. G., Okbay, A., Rietveld, C. A., Timshel, P. N., Trzaskowski, M., De Vlaming, R., Zünd, C. L., Bao, Y., Buzdugan, L., Caplin, A. H. and 72 moreLinnér, R. K., Biroli, P., Kong, E., Meddens, S. F. W., Wedow, R., Fontana, M. A., Lebreton, M., Tino, S. P., Abdellaoui, A., Hammerschlag, A. R., Nivard, M. G., Okbay, A., Rietveld, C. A., Timshel, P. N., Trzaskowski, M., De Vlaming, R., Zünd, C. L., Bao, Y., Buzdugan, L., Caplin, A. H., Chen, C.-Y., Eibich, P., Fontanillas, P., Gonzalez, J. R., Joshi, P. K., Karhunen, V., Kleinman, A., Levin, R. Z., Lill, C. M., Meddens, G. A., Muntané, G., Sanchez-Roige, S., Van Rooij, F. J., Taskesen, E., Wu, Y., Zhang, F., 23and Me Research Team, eQTLgen Consortium, International Cannabis Consortium, Social Science Genetic Association Consortium, Auton, A., Boardman, J. D., Clark, D. W., Conlin, A., Dolan, C. C., Fischbacher, U., Groenen, P. J. F., Harris, K. M., Hasler, G., Hofman, A., Ikram, M. A., Jain, S., Karlsson, R., Kessler, R. C., Kooyman, M., MacKillop, J., Männikkö, M., Morcillo-Suarez, C., McQueen, M. B., Schmidt, K. M., Smart, M. C., Sutter, M., Thurik, A. R., Uitterlinden, A. G., White, J., De Wit, H., Yang, J., Bertram, L., Boomsma, D. I., Esko, T., Fehr, E., Hinds, D. A., Johannesson, M., Kumari, M., Laibson, D., Magnusson, P. K. E., Meyer, M. N., Navarro, A., Palmer, A. A., Pers, T. H., Posthuma, D., Schunk, D., Stein, M. B., Svento, R., Tiemeier, H., Timmers, P. R. H. J., Turley, P., Ursano, R. J., Wagner, G. G., Wilson, J. F., Gratten, J., Lee, J. J., Cesarini, D., Benjamin, D. J., Koellinger, P. D., & Beauchamp, J. P. (2019). Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences. Nature Genetics, 51, 245-257. doi:10.1038/s41588-018-0309-3.
  • Middeldorp, C. M., Felix, J. F., Mahajan, A., EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium, Early Growth Genetics (EGG) consortium, & McCarthy, M. I. (2019). The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia: Design, results and future prospects. European Journal of Epidemiology, 34(3), 279-300. doi:10.1007/s10654-019-00502-9.

    Abstract

    The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
  • Tilot, A. K., Vino, A., Kucera, K. S., Carmichael, D. A., Van den Heuvel, L., Den Hoed, J., Sidoroff-Dorso, A. V., Campbell, A., Porteous, D. J., St Pourcain, B., Van Leeuwen, T. M., Ward, J., Rouw, R., Simner, J., & Fisher, S. E. (2019). Investigating genetic links between grapheme-colour synaesthesia and neuropsychiatric traits. Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences, 374: 20190026. doi:10.1098/rstb.2019.0026.

    Abstract

    Synaesthesia is a neurological phenomenon affecting perception, where triggering stimuli (e.g. letters and numbers) elicit unusual secondary sensory experiences (e.g. colours). Family-based studies point to a role for genetic factors in the development of this trait. However, the contributions of common genomic variation to synaesthesia have not yet been investigated. Here, we present the SynGenes cohort, the largest genotyped collection of unrelated people with grapheme–colour synaesthesia (n = 723). Synaesthesia has been associated with a range of other neuropsychological traits, including enhanced memory and mental imagery, as well as greater sensory sensitivity. Motivated by the prior literature on putative trait overlaps, we investigated polygenic scores derived from published genome-wide scans of schizophrenia and autism spectrum disorder (ASD), comparing our SynGenes cohort to 2181 non-synaesthetic controls. We found a very slight association between schizophrenia polygenic scores and synaesthesia (Nagelkerke's R2 = 0.0047, empirical p = 0.0027) and no significant association for scores related to ASD (Nagelkerke's R2 = 0.00092, empirical p = 0.54) or body mass index (R2 = 0.00058, empirical p = 0.60), included as a negative control. As sample sizes for studying common genomic variation continue to increase, genetic investigations of the kind reported here may yield novel insights into the shared biology between synaesthesia and other traits, to complement findings from neuropsychology and brain imaging.

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  • Verhoef, E., Demontis, D., Burgess, S., Shapland, C. Y., Dale, P. S., Okbay, A., Neale, B. M., Faraone, S. V., iPSYCH-Broad-PGC ADHD Consortium, Stergiakouli, E., Davey Smith, G., Fisher, S. E., Borglum, A., & St Pourcain, B. (2019). Disentangling polygenic associations between Attention-Deficit/Hyperactivity Disorder, educational attainment, literacy and language. Translational Psychiatry, 9: 35. doi:10.1038/s41398-018-0324-2.

    Abstract

    Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10−8), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10−5). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10−6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.

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    41398_2018_324_MOESM1_ESM.docx
  • Howe, L. J., Lee, M. K., Sharp, G. C., Smith, G. D. W., St Pourcain, B., Shaffer, J. R., Ludwig, K. U., Mangold, E., Marazita, M. L., Feingold, E., Zhurov, A., Stergiakouli, E., Sandy, J., Richmond, S., Weinberg, S. M., Hemani, G., & Lewis, S. J. (2018). Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology. PLoS Genetics, 14(8): e1007501. doi:10.1371/journal.pgen.1007501.

    Abstract

    There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 2x10-5). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.
  • Lee, J. J., Wedow, R., Okbay, A., Kong, E., Maghzian, O., Zacher, M., Nguyen-Viet, T. A., Bowers, P., Sidorenko, J., Linnér, R. K., Fontana, M. A., Kundu, T., Lee, C., Li, H., Li, R., Royer, R., Timshel, P. N., Walters, R. K., Willoughby, E. A., Yengo, L. and 57 moreLee, J. J., Wedow, R., Okbay, A., Kong, E., Maghzian, O., Zacher, M., Nguyen-Viet, T. A., Bowers, P., Sidorenko, J., Linnér, R. K., Fontana, M. A., Kundu, T., Lee, C., Li, H., Li, R., Royer, R., Timshel, P. N., Walters, R. K., Willoughby, E. A., Yengo, L., 23andMe Research Team, COGENT (Cognitive Genomics Consortium), Social Science Genetic Association Consortium, Alver, M., Bao, Y., Clark, D. W., Day, F. R., Furlotte, N. A., Joshi, P. K., Kemper, K. E., Kleinman, A., Langenberg, C., Mägi, R., Trampush, J. W., Verma, S. S., Wu, Y., Lam, M., Zhao, J. H., Zheng, Z., Boardman, J. D., Campbell, H., Freese, J., Harris, K. M., Hayward, C., Herd, P., Kumari, M., Lencz, T., Luan, J., Malhotra, A. K., Metspalu, A., Milani, L., Ong, K. K., Perry, J. R. B., Porteous, D. J., Ritchie, M. D., Smart, M. C., Smith, B. H., Tung, J. Y., Wareham, N. J., Wilson, J. F., Beauchamp, J. P., Conley, D. C., Esko, T., Lehrer, S. F., Magnusson, P. K. E., Oskarsson, S., Pers, T. H., Robinson, M. R., Thom, K., Watson, C., Chabris, C. F., Meyer, M. N., Laibson, D. I., Yang, J., Johannesson, M., Koellinger, P. D., Turley, P., Visscher, P. M., Benjamin, D. J., & Cesarini, D. (2018). Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. Nature Genetics, 50(8), 1112-1121. doi:10.1038/s41588-018-0147-3.

    Abstract

    Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance in educational attainment and 7–10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
  • Ligthart, S., Vaez, A., Võsa, U., Stathopoulou, M. G., De Vries, P. S., Prins, B. P., Van der Most, P. J., Tanaka, T., Naderi, E., Rose, L. M., Wu, Y., Karlsson, R., Barbalic, M., Lin, H., Pool, R., Zhu, G., Macé, A., Sidore, C., Trompet, S., Mangino, M. and 267 moreLigthart, S., Vaez, A., Võsa, U., Stathopoulou, M. G., De Vries, P. S., Prins, B. P., Van der Most, P. J., Tanaka, T., Naderi, E., Rose, L. M., Wu, Y., Karlsson, R., Barbalic, M., Lin, H., Pool, R., Zhu, G., Macé, A., Sidore, C., Trompet, S., Mangino, M., Sabater-Lleal, M., Kemp, J. P., Abbasi, A., Kacprowski, T., Verweij, N., Smith, A. V., Huang, T., Marzi, C., Feitosa, M. F., Lohman, K. K., Kleber, M. E., Milaneschi, Y., Mueller, C., Huq, M., Vlachopoulou, E., Lyytikäinen, L.-P., Oldmeadow, C., Deelen, J., Perola, M., Zhao, J. H., Feenstra, B., LifeLines Cohort Study, Amini, M., CHARGE Inflammation Working Group, Lahti, J., Schraut, K. E., Fornage, M., Suktitipat, B., Chen, W.-M., Li, X., Nutile, T., Malerba, G., Luan, J., Bak, T., Schork, N., Del Greco M., F., Thiering, E., Mahajan, A., Marioni, R. E., Mihailov, E., Eriksson, J., Ozel, A. B., Zhang, W., Nethander, M., Cheng, Y.-C., Aslibekyan, S., Ang, W., Gandin, I., Yengo, L., Portas, L., Kooperberg, C., Hofer, E., Rajan, K. B., Schurmann, C., Den Hollander, W., Ahluwalia, T. S., Zhao, J., Draisma, H. H. M., Ford, I., Timpson, N., Teumer, A., Huang, H., Wahl, S., Liu, Y., Huang, J., Uh, H.-W., Geller, F., Joshi, P. K., Yanek, L. R., Trabetti, E., Lehne, B., Vozzi, D., Verbanck, M., Biino, G., Saba, Y., Meulenbelt, I., O’Connell, J. R., Laakso, M., Giulianini, F., Magnusson, P. K. E., Ballantyne, C. M., Hottenga, J. J., Montgomery, G. W., Rivadineira, F., Rueedi, R., Steri, M., Herzig, K.-H., Stott, D. J., Menni, C., Franberg, M., St Pourcain, B., Felix, S. B., Pers, T. H., Bakker, S. J. L., Kraft, P., Peters, A., Vaidya, D., Delgado, G., Smit, J. H., Großmann, V., Sinisalo, J., Seppälä, I., Williams, S. R., Holliday, E. G., Moed, M., Langenberg, C., Räikkönen, K., Ding, J., Campbell, H., Sale, M. M., Chen, Y.-D.-I., James, A. L., Ruggiero, D., Soranzo, N., Hartman, C. A., Smith, E. N., Berenson, G. S., Fuchsberger, C., Hernandez, D., Tiesler, C. M. T., Giedraitis, V., Liewald, D., Fischer, K., Mellström, D., Larsson, A., Wang, Y., Scott, W. R., Lorentzon, M., Beilby, J., Ryan, K. A., Pennell, C. E., Vuckovic, D., Balkau, B., Concas, M. P., Schmidt, R., Mendes de Leon, C. F., Bottinger, E. P., Kloppenburg, M., Paternoster, L., Boehnke, M., Musk, A. W., Willemsen, G., Evans, D. M., Madden, P. A. F., Kähönen, M., Kutalik, Z., Zoledziewska, M., Karhunen, V., Kritchevsky, S. B., Sattar, N., Lachance, G., Clarke, R., Harris, T. B., Raitakari, O. T., Attia, J. R., Van Heemst, D., Kajantie, E., Sorice, R., Gambaro, G., Scott, R. A., Hicks, A. A., Ferrucci, L., Standl, M., Lindgren, C. M., Starr, J. M., Karlsson, M., Lind, L., Li, J. Z., Chambers, J. C., Mori, T. A., De Geus, E. J. C. N., Heath, A. C., Martin, N. G., Auvinen, J., Buckley, B. M., De Craen, A. J. M., Waldenberger, M., Strauch, K., Meitinger, T., Scott, R. J., McEvoy, M., Beekman, M., Bombieri, C., Ridker, P. M., Mohlke, K. L., Pedersen, N. L., Morrison, A. C., Boomsma, D. I., Whitfield, J. B., Strachan, D. P., Hofman, A., Vollenweider, P., Cucca, F., Jarvelin, M.-R., Jukema, J. W., Spector, T. D., Hamsten, A., Zeller, T., Uitterlinden, A. G., Nauck, M., Gudnason, V., Qi, L., Grallert, H., Borecki, I. B., Rotter, J. I., März, W., Wild, P. S., Lokki, M.-L., Boyle, M., Salomaa, V., Melbye, M., Eriksson, J. G., Wilson, J. F., Penninx, B. W. J. H., Becker, D. M., Worrall, B. B., Gibson, G., Krauss, R. M., Ciullo, M., Zaza, G., Wareham, N. J., Oldehinkel, A. J., Palmer, L. J., Murray, S. S., Pramstaller, P. P., Bandinelli, S., Heinrich, J., Ingelsson, E., Deary, I. J., Ma¨gi, R., Vandenput, L., Van der Harst, P., Desch, K. C., Kooner, J. S., Ohlsson, C., Hayward, C., Lehtima¨ki, T., Shuldiner, A. R., Arnett, D. K., Beilin, L. J., Robino, A., Froguel, P., Pirastu, M., Jess, T., Koenig, W., Loos, R. J. F., Evans, D. A., Schmidt, H., Smith, G. D., Slagboom, P. E., Eiriksdottir, G., Morris, A. P., Psaty, B. M., Tracy, R. P., Nolte, I. M., Boerwinkle, E., Visvikis-Siest, S., Reiner, A. P., Gross, M., Bis, J. C., Franke, L., Franco, O. H., Benjamin, E. J., Chasman, D. I., Dupuis, J., Snieder, H., Dehghan, A., & Alizadeh, B. Z. (2018). Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. The American Journal of Human Genetics, 103(5), 691-706. doi:10.1016/j.ajhg.2018.09.009.

    Abstract

    C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10−8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
  • Mandy, W., Pellicano, L., St Pourcain, B., Skuse, D., & Heron, J. (2018). The development of autistic social traits across childhood and adolescence in males and females. The Journal of Child Psychology and Psychiatry, 59(11), 1143-1151. doi:10.1111/jcpp.12913.

    Abstract

    Background Autism is a dimensional condition, representing the extreme end of a continuum of social competence that extends throughout the general population. Currently, little is known about how autistic social traits (ASTs), measured across the full spectrum of severity, develop during childhood and adolescence, including whether there are developmental differences between boys and girls. Therefore, we sought to chart the trajectories of ASTs in the general population across childhood and adolescence, with a focus on gender differences. Methods Participants were 9,744 males (n = 4,784) and females (n = 4,960) from ALSPAC, a UK birth cohort study. ASTs were assessed when participants were aged 7, 10, 13 and 16 years, using the parent‐report Social Communication Disorders Checklist. Data were modelled using latent growth curve analysis. Results Developmental trajectories of males and females were nonlinear, showing a decline from 7 to 10 years, followed by an increase between 10 and 16 years. At 7 years, males had higher levels of ASTs than females (mean raw score difference = 0.88, 95% CI [.72, 1.04]), and were more likely (odds ratio [OR] = 1.99; 95% CI, 1.82, 2.16) to score in the clinical range on the SCDC. By 16 years this gender difference had disappeared: males and females had, on average, similar levels of ASTs (mean difference = 0.00, 95% CI [−0.19, 0.19]) and were equally likely to score in the SCDC's clinical range (OR = 0.91, 95% CI, 0.73, 1.10). This was the result of an increase in females’ ASTs between 10 and 16 years. Conclusions There are gender‐specific trajectories of autistic social impairment, with females more likely than males to experience an escalation of ASTs during early‐ and midadolescence. It remains to be discovered whether the observed female adolescent increase in ASTs represents the genuine late onset of social difficulties or earlier, subtle, pre‐existing difficulties becoming more obvious.

    Additional information

    jcpp12913-sup-0001-supinfo.docx
  • St Pourcain, B., Robinson, E. B., Anttila, V., Sullivan, B. B., Maller, J., Golding, J., Skuse, D., Ring, S., Evans, D. M., Zammit, S., Fisher, S. E., Neale, B. M., Anney, R., Ripke, S., Hollegaard, M. V., Werge, T., iPSYCH-SSI-Broad Autism Group, Ronald, A., Grove, J., Hougaard, D. M., Børglum, A. D. and 3 moreSt Pourcain, B., Robinson, E. B., Anttila, V., Sullivan, B. B., Maller, J., Golding, J., Skuse, D., Ring, S., Evans, D. M., Zammit, S., Fisher, S. E., Neale, B. M., Anney, R., Ripke, S., Hollegaard, M. V., Werge, T., iPSYCH-SSI-Broad Autism Group, Ronald, A., Grove, J., Hougaard, D. M., Børglum, A. D., Mortensen, P. B., Daly, M., & Davey Smith, G. (2018). ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social-communication difficulties. Molecular Psychiatry, 23, 263-270. doi:10.1038/mp.2016.198.

    Abstract

    Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether overlap in common genetic in fluences between these clinical conditions and impairments in social communication depends on the developmental stage of the assessed trait. Social communication difficulties were measured in typically-developing youth (Avon Longitudinal Study of Parents and Children,N⩽5553, longitudinal assessments at 8, 11, 14 and 17 years) using the Social Communication Disorder Checklist. Data on clinical ASD (PGC-ASD: 5305 cases, 5305 pseudo-controls; iPSYCH-ASD: 7783 cases, 11 359 controls) and schizophrenia (PGC-SCZ2: 34 241 cases, 45 604 controls, 1235 trios) were either obtained through the Psychiatric Genomics Consortium (PGC) or the Danish iPSYCH project. Overlap in genetic in fluences between ASD and social communication difficulties during development decreased with age, both in the PGC-ASD and the iPSYCH-ASD sample. Genetic overlap between schizophrenia and social communication difficulties, by contrast, persisted across age, as observed within two independent PGC-SCZ2 subsamples, and showed an increase in magnitude for traits assessed during later adolescence. ASD- and schizophrenia-related polygenic effects were unrelated to each other and changes in trait-disorder links reflect the heterogeneity of genetic factors in fluencing social communication difficulties during childhood versus later adolescence. Thus, both clinical ASD and schizophrenia share some genetic in fluences with impairments in social communication, but reveal distinct developmental profiles in their genetic links, consistent with the onset of clinical symptoms

    Additional information

    mp2016198x1.docx
  • St Pourcain, B., Eaves, L. J., Ring, S. M., Fisher, S. E., Medland, S., Evans, D. M., & Smith, G. D. (2018). Developmental changes within the genetic architecture of social communication behaviour: A multivariate study of genetic variance in unrelated individuals. Biological Psychiatry, 83(7), 598-606. doi:10.1016/j.biopsych.2017.09.020.

    Abstract

    Background: Recent analyses of trait-disorder overlap suggest that psychiatric dimensions may relate to distinct sets of genes that exert their maximum influence during different periods of development. This includes analyses of social-communciation difficulties that share, depending on their developmental stage, stronger genetic links with either Autism Spectrum Disorder or schizophrenia. Here we developed a multivariate analysis framework in unrelated individuals to model directly the developmental profile of genetic influences contributing to complex traits, such as social-communication difficulties, during a ~10-year period spanning childhood and adolescence. Methods: Longitudinally assessed quantitative social-communication problems (N ≤ 5,551) were studied in participants from a UK birth cohort (ALSPAC, 8 to 17 years). Using standardised measures, genetic architectures were investigated with novel multivariate genetic-relationship-matrix structural equation models (GSEM) incorporating whole-genome genotyping information. Analogous to twin research, GSEM included Cholesky decomposition, common pathway and independent pathway models. Results: A 2-factor Cholesky decomposition model described the data best. One genetic factor was common to SCDC measures across development, the other accounted for independent variation at 11 years and later, consistent with distinct developmental profiles in trait-disorder overlap. Importantly, genetic factors operating at 8 years explained only ~50% of the genetic variation at 17 years. Conclusion: Using latent factor models, we identified developmental changes in the genetic architecture of social-communication difficulties that enhance the understanding of ASD and schizophrenia-related dimensions. More generally, GSEM present a framework for modelling shared genetic aetiologies between phenotypes and can provide prior information with respect to patterns and continuity of trait-disorder overlap
  • Nivard, M. G., Gage, S. H., Hottenga, J. J., van Beijsterveldt, C. E. M., Abdellaoui, A., Bartels, M., Baselmans, B. M. L., Ligthart, L., St Pourcain, B., Boomsma, D. I., Munafò, M. R., & Middeldorp, C. M. (2017). Genetic overlap between schizophrenia and developmental psychopathology: Longitudinal and multivariate polygenic risk prediction of common psychiatric traits during development. Schizophrenia Bulletin, 43(6), 1197-1207. doi:10.1093/schbul/sbx031.

    Abstract

    Background: Several nonpsychotic psychiatric disorders in childhood and adolescence can precede the onset of schizophrenia, but the etiology of this relationship remains unclear. We investigated to what extent the association between schizophrenia and psychiatric disorders in childhood is explained by correlated genetic risk factors. Methods: Polygenic risk scores (PRS), reflecting an individual’s genetic risk for schizophrenia, were constructed for 2588 children from the Netherlands Twin Register (NTR) and 6127 from the Avon Longitudinal Study of Parents And Children (ALSPAC). The associations between schizophrenia PRS and measures of anxiety, depression, attention deficit hyperactivity disorder (ADHD), and oppositional defiant disorder/conduct disorder (ODD/CD) were estimated at age 7, 10, 12/13, and 15 years in the 2 cohorts. Results were then meta-analyzed, and a meta-regression analysis was performed to test differences in effects sizes over, age and disorders. Results: Schizophrenia PRS were associated with childhood and adolescent psychopathology. Meta-regression analysis showed differences in the associations over disorders, with the strongest association with childhood and adolescent depression and a weaker association for ODD/CD at age 7. The associations increased with age and this increase was steepest for ADHD and ODD/CD. Genetic correlations varied between 0.10 and 0.25. Conclusion: By optimally using longitudinal data across diagnoses in a multivariate meta-analysis this study sheds light on the development of childhood disorders into severe adult psychiatric disorders. The results are consistent with a common genetic etiology of schizophrenia and developmental psychopathology as well as with a stronger shared genetic etiology between schizophrenia and adolescent onset psychopathology.
  • Nivard, M. G., Lubke, G. H., Dolan, C. V., Evans, D. M., St Pourcain, B., Munafo, M. R., & Middeldorp, C. M. (2017). Joint developmental trajectories of internalizing and externalizing disorders between childhood and adolescence. Development and Psychopathology, 29(3), 919-928. doi:10.1017/S0954579416000572.

    Abstract

    This study sought to identify trajectories of DSM-IV based internalizing (INT) and externalizing (EXT) problem scores across childhood and adolescence and to provide insight into the comorbidity by modeling the co-occurrence of INT and EXT trajectories. INT and EXT were measured repeatedly between age 7 and age 15 years in over 7,000 children and analyzed using growth mixture models. Five trajectories were identified for both INT and EXT, including very low, low, decreasing, and increasing trajectories. In addition, an adolescent onset trajectory was identified for INT and a stable high trajectory was identified for EXT. Multinomial regression showed that similar EXT and INT trajectories were associated. However, the adolescent onset INT trajectory was independent of high EXT trajectories, and persisting EXT was mainly associated with decreasing INT. Sex and early life environmental risk factors predicted EXT and, to a lesser extent, INT trajectories. The association between trajectories indicates the need to consider comorbidity when a child presents with INT or EXT disorders, particularly when symptoms start early. This is less necessary when INT symptoms start at adolescence. Future studies should investigate the etiology of co-occurring INT and EXT and the specific treatment needs of these severely affected children.
  • Stergiakouli, E., Martin, J., Hamshere, M. L., Heron, J., St Pourcain, B., Timpson, N. J., Thapar, A., & Smith, G. D. (2017). Association between polygenic risk scores for attention-deficit hyperactivity disorder and educational and cognitive outcomes in the general population. International Journal of Epidemiology, 46(2), 421-428. doi:10.1093/ije/dyw216.

    Abstract

    Background: Children with a diagnosis of attention-deficit hyperactivity disorder (ADHD) have lower cognitive ability and are at risk of adverse educational outcomes; ADHD genetic risks have been found to predict childhood cognitive ability and other neurodevelopmental traits in the general population; thus genetic risks might plausibly also contribute to cognitive ability later in development and to educational underachievement. Methods: We generated ADHD polygenic risk scores in the Avon Longitudinal Study of Parents and Children participants (maximum N: 6928 children and 7280 mothers) based on the results of a discovery clinical sample, a genome-wide association study of 727 cases with ADHD diagnosis and 5081 controls. We tested if ADHD polygenic risk scores were associated with educational outcomes and IQ in adolescents and their mothers. Results: High ADHD polygenic scores in adolescents were associated with worse educational outcomes at Key Stage 3 [national tests conducted at age 13–14 years; β = −1.4 (−2.0 to −0.8), P = 2.3 × 10−6), at General Certificate of Secondary Education exams at age 15–16 years (β = −4.0 (−6.1 to −1.9), P = 1.8 × 10−4], reduced odds of sitting Key Stage 5 examinations at age 16–18 years [odds ratio (OR) = 0.90 (0.88 to 0.97), P = 0.001] and lower IQ scores at age 15.5 [β = −0.8 (−1.2 to −0.4), P = 2.4 × 10−4]. Moreover, maternal ADHD polygenic scores were associated with lower maternal educational achievement [β = −0.09 (−0.10 to −0.06), P = 0.005] and lower maternal IQ [β = −0.6 (−1.2 to −0.1), P = 0.03]. Conclusions: ADHD diagnosis risk alleles impact on functional outcomes in two generations (mother and child) and likely have intergenerational environmental effects.
  • Stergiakouli, E., Smith, G. D., Martin, J., Skuse, D. H., Viechtbauer, W., Ring, S. M., Ronald, A., Evans, D. E., Fisher, S. E., Thapar, A., & St Pourcain, B. (2017). Shared genetic influences between dimensional ASD and ADHD symptoms during child and adolescent development. Molecular Autism, 8: 18. doi:10.1186/s13229-017-0131-2.

    Abstract

    Background: Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) symptoms have been reported. Cross-trait genetic relationships are, however, subject to dynamic changes during development. We investigated the continuity of genetic overlap between ASD and ADHD symptoms in a general population sample during childhood and adolescence. We also studied uni- and cross-dimensional trait-disorder links with respect to genetic ADHD and ASD risk. Methods: Social-communication difficulties (N ≤ 5551, Social and Communication Disorders Checklist, SCDC) and combined hyperactive-impulsive/inattentive ADHD symptoms (N ≤ 5678, Strengths and Difficulties Questionnaire, SDQ-ADHD) were repeatedly measured in a UK birth cohort (ALSPAC, age 7 to 17 years). Genome-wide summary statistics on clinical ASD (5305 cases; 5305 pseudo-controls) and ADHD (4163 cases; 12,040 controls/pseudo-controls) were available from the Psychiatric Genomics Consortium. Genetic trait variances and genetic overlap between phenotypes were estimated using genome-wide data. Results: In the general population, genetic influences for SCDC and SDQ-ADHD scores were shared throughout development. Genetic correlations across traits reached a similar strength and magnitude (cross-trait rg ≤ 1, pmin = 3 × 10−4) as those between repeated measures of the same trait (within-trait rg ≤ 0.94, pmin = 7 × 10−4). Shared genetic influences between traits, especially during later adolescence, may implicate variants in K-RAS signalling upregulated genes (p-meta = 6.4 × 10−4). Uni-dimensionally, each population-based trait mapped to the expected behavioural continuum: risk-increasing alleles for clinical ADHD were persistently associated with SDQ-ADHD scores throughout development (marginal regression R2 = 0.084%). An age-specific genetic overlap between clinical ASD and social-communication difficulties during childhood was also shown, as per previous reports. Cross-dimensionally, however, neither SCDC nor SDQ-ADHD scores were linked to genetic risk for disorder. Conclusions: In the general population, genetic aetiologies between social-communication difficulties and ADHD symptoms are shared throughout child and adolescent development and may implicate similar biological pathways that co-vary during development. Within both the ASD and the ADHD dimension, population-based traits are also linked to clinical disorder, although much larger clinical discovery samples are required to reliably detect cross-dimensional trait-disorder relationships.
  • Tachmazidou, I., Süveges, D., Min, J. L., Ritchie, G. R. S., Steinberg, J., Walter, K., Iotchkova, V., Schwartzentruber, J., Huang, J., Memari, Y., McCarthy, S., Crawford, A. A., Bombieri, C., Cocca, M., Farmaki, A.-E., Gaunt, T. R., Jousilahti, P., Kooijman, M. N., Lehne, B., Malerba, G. and 83 moreTachmazidou, I., Süveges, D., Min, J. L., Ritchie, G. R. S., Steinberg, J., Walter, K., Iotchkova, V., Schwartzentruber, J., Huang, J., Memari, Y., McCarthy, S., Crawford, A. A., Bombieri, C., Cocca, M., Farmaki, A.-E., Gaunt, T. R., Jousilahti, P., Kooijman, M. N., Lehne, B., Malerba, G., Männistö, S., Matchan, A., Medina-Gomez, C., Metrustry, S. J., Nag, A., Ntalla, I., Paternoster, L., Rayner, N. W., Sala, C., Scott, W. R., Shihab, H. A., Southam, L., St Pourcain, B., Traglia, M., Trajanoska, K., Zaza, G., Zhang, W., Artigas, M. S., Bansal, N., Benn, M., Chen, Z., Danecek, P., Lin, W.-Y., Locke, A., Luan, J., Manning, A. K., Mulas, A., Sidore, C., Tybjaerg-Hansen, A., Varbo, A., Zoledziewska, M., Finan, C., Hatzikotoulas, K., Hendricks, A. E., Kemp, J. P., Moayyeri, A., Panoutsopoulou, K., Szpak, M., Wilson, S. G., Boehnke, M., Cucca, F., Di Angelantonio, E., Langenberg, C., Lindgren, C., McCarthy, M. I., Morris, A. P., Nordestgaard, B. G., Scott, R. A., Tobin, M. D., Wareham, N. J., Burton, P., Chambers, J. C., Smith, G. D., Dedoussis, G., Felix, J. F., Franco, O. H., Gambaro, G., Gasparini, P., Hammond, C. J., Hofman, A., Jaddoe, V. W. V., Kleber, M., Kooner, J. S., Perola, M., Relton, C., Ring, S. M., Rivadeneira, F., Salomaa, V., Spector, T. D., Stegle, O., Toniolo, D., Uitterlinden, A. G., Barroso, I., Greenwood, C. M. T., Perry, J. R. B., Walker, B. R., Butterworth, A. S., Xue, Y., Durbin, R., Small, K. S., Soranzo, N., Timpson, N. J., & Zeggini, E. (2017). Whole-Genome Sequencing coupled to imputation discovers genetic signals for anthropometric traits. The American Journal of Human Genetics, 100(6), 865-884. doi:10.1016/j.ajhg.2017.04.014.

    Abstract

    Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.
  • Ho, Y. Y. W., Evans, D. M., Montgomery, G. W., Henders, A. K., Kemp, J. P., Timpson, N. J., St Pourcain, B., Heath, A. C., Madden, P. A. F., Loesch, D. Z., McNevin, D., Daniel, R., Davey-Smith, G., Martin, N. G., & Medland, S. E. (2016). Common genetic variants influence whorls in fingerprint patterns. Journal of Investigative Dermatology, 136(4), 859-862. doi:10.1016/j.jid.2015.10.062.
  • Fan, Q., Guo, X., Tideman, J. W. L., Williams, K. M., Yazar, S., Hosseini, S. M., Howe, L. D., St Pourcain, B., Evans, D. M., Timpson, N. J., McMahon, G., Hysi, P. G., Krapohl, E., Wang, Y. X., Jonas, J. B., Baird, P. N., Wang, J. J., Cheng, C. Y., Teo, Y. Y., Wong, T. Y. and 17 moreFan, Q., Guo, X., Tideman, J. W. L., Williams, K. M., Yazar, S., Hosseini, S. M., Howe, L. D., St Pourcain, B., Evans, D. M., Timpson, N. J., McMahon, G., Hysi, P. G., Krapohl, E., Wang, Y. X., Jonas, J. B., Baird, P. N., Wang, J. J., Cheng, C. Y., Teo, Y. Y., Wong, T. Y., Ding, X., Wojciechowski, R., Young, T. L., Parssinen, O., Oexle, K., Pfeiffer, N., Bailey-Wilson, J. E., Paterson, A. D., Klaver, C. C. W., Plomin, R., Hammond, C. J., Mackey, D. A., He, M. G., Saw, S. M., Williams, C., Guggenheim, J. A., & Cream, C. (2016). Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium. Scientific Reports, 6: 25853. doi:10.1038/srep25853.

    Abstract

    Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).

    Additional information

    srep25853-s1.pdf
  • Fan, Q., Verhoeven, V. J., Wojciechowski, R., Barathi, V. A., Hysi, P. G., Guggenheim, J. A., Höhn, R., Vitart, V., Khawaja, A. P., Yamashiro, K., Hosseini, S. M., Lehtimäki, T., Lu, Y., Haller, T., Xie, J., Delcourt, C., Pirastu, M., Wedenoja, J., Gharahkhani, P., Venturini, C. and 83 moreFan, Q., Verhoeven, V. J., Wojciechowski, R., Barathi, V. A., Hysi, P. G., Guggenheim, J. A., Höhn, R., Vitart, V., Khawaja, A. P., Yamashiro, K., Hosseini, S. M., Lehtimäki, T., Lu, Y., Haller, T., Xie, J., Delcourt, C., Pirastu, M., Wedenoja, J., Gharahkhani, P., Venturini, C., Miyake, M., Hewitt, A. W., Guo, X., Mazur, J., Huffman, J. E., Williams, K. M., Polasek, O., Campbell, H., Rudan, I., Vatavuk, Z., Wilson, J. F., Joshi, P. K., McMahon, G., St Pourcain, B., Evans, D. M., Simpson, C. L., Schwantes-An, T.-H., Igo, R. P., Mirshahi, A., Cougnard-Gregoire, A., Bellenguez, C., Blettner, M., Raitakari, O., Kähönen, M., Seppälä, I., Zeller, T., Meitinger, T., Ried, J. S., Gieger, C., Portas, L., Van Leeuwen, E. M., Amin, N., Uitterlinden, A. G., Rivadeneira, F., Hofman, A., Vingerling, J. R., Wang, Y. X., Wang, X., Boh, E.-T.-H., Ikram, M. K., Sabanayagam, C., Gupta, P., Tan, V., Zhou, L., Ho, C. E., Lim, W., Beuerman, R. W., Siantar, R., Tai, E.-S., Vithana, E., Mihailov, E., Khor, C.-C., Hayward, C., Luben, R. N., Foster, P. J., Klein, B. E., Klein, R., Wong, H.-S., Mitchell, P., Metspalu, A., Aung, T., Young, T. L., He, M., Pärssinen, O., Van Duijn, C. M., Wang, J. J., Williams, C., Jonas, J. B., Teo, Y.-Y., Mackey, D. A., Oexle, K., Yoshimura, N., Paterson, A. D., Pfeiffer, N., Wong, T.-Y., Baird, P. N., Stambolian, D., Bailey-Wilson, J. E., Cheng, C.-Y., Hammond, C. J., Klaver, C. C., Saw, S.-M., & Consortium for Refractive Error and Myopia (CREAM) (2016). Meta-analysis of gene–environment-wide association scans accounting for education level identifies additional loci for refractive error. Nature Communications, 7: 11008. doi:10.1038/ncomms11008.

    Abstract

    Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10−5), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia

    Additional information

    Fan_etal_2016sup.pdf
  • Hugh-Jones, D., Verweij, K. J. H., St Pourcain, B., & Abdellaoui, A. (2016). Assortative mating on educational attainment leads to genetic spousal resemblance for causal alleles. Intelligence, 59, 103-108. doi:10.1016/j.intell.2016.08.005.

    Abstract

    We examined whether assortative mating for educational attainment (“like marries like”) can be detected in the genomes of ~ 1600 UK spouse pairs of European descent. Assortative mating on heritable traits like educational attainment increases the genetic variance and heritability of the trait in the population, which may increase social inequalities. We test for genetic assortative mating in the UK on educational attainment, a phenotype that is indicative of socio-economic status and has shown substantial levels of assortative mating. We use genome-wide allelic effect sizes from a large genome-wide association study on educational attainment (N ~ 300 k) to create polygenic scores that are predictive of educational attainment in our independent sample (r = 0.23, p < 2 × 10− 16). The polygenic scores significantly predict partners' educational outcome (r = 0.14, p = 4 × 10− 8 and r = 0.19, p = 2 × 10− 14, for prediction from males to females and vice versa, respectively), and are themselves significantly correlated between spouses (r = 0.11, p = 7 × 10− 6). Our findings provide molecular genetic evidence for genetic assortative mating on education in the UK
  • Middeldorp, C. M., Hammerschlag, A. R., Ouwens, K. G., Groen-Blokhuis, M. M., St Pourcain, B., Greven, C. U., Pappa, I., Tiesler, C. M. T., Ang, W., Nolte, I. M., Vilor-Tejedor, N., Bacelis, J., Ebejer, J. L., Zhao, H., Davies, G. E., Ehli, E. A., Evans, D. M., Fedko, I. O., Guxens, M., Hottenga, J.-J. and 31 moreMiddeldorp, C. M., Hammerschlag, A. R., Ouwens, K. G., Groen-Blokhuis, M. M., St Pourcain, B., Greven, C. U., Pappa, I., Tiesler, C. M. T., Ang, W., Nolte, I. M., Vilor-Tejedor, N., Bacelis, J., Ebejer, J. L., Zhao, H., Davies, G. E., Ehli, E. A., Evans, D. M., Fedko, I. O., Guxens, M., Hottenga, J.-J., Hudziak, J. J., Jugessur, A., Kemp, J. P., Krapohl, E., Martin, N. G., Murcia, M., Myhre, R., Ormel, J., Ring, S. M., Standl, M., Stergiakouli, E., Stoltenberg, C., Thiering, E., Timpson, N. J., Trzaskowski, M., van der Most, P. J., Wang, C., EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium, Psychiatric Genomics Consortium ADHD Working Group, Nyholt, D. R., Medland, S. E., Neale, B., Jacobsson, B., Sunyer, J., Hartman, C. A., Whitehouse, A. J. O., Pennell, C. E., Heinrich, J., Plomin, R., Smith, G. D., Tiemeier, H., Posthuma, D., & Boomsma, D. I. (2016). A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Paediatric Cohorts. Journal of the American Academy of Child & Adolescent Psychiatry, 55(10), 896-905. doi:10.1016/j.jaac.2016.05.025.

    Abstract

    Objective To elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis. Method Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (< 13 years) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated. Results SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46×10-6 and 2.66×10-6). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96. Conclusion The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and improve statistical power for identifying genetic variants.
  • Okbay, A., Beauchamp, J. P., Fontana, M. A., Lee, J. J., Pers, T. H., Rietveld, C. A., Turley, P., Chen, G. B., Emilsson, V., Meddens, S. F. W., Oskarsson, S., Pickrell, J. K., Thom, K., Timshel, P., De Vlaming, R., Abdellaoui, A., Ahluwalia, T. S., Bacelis, J., Baumbach, C., Bjornsdottir, G. and 236 moreOkbay, A., Beauchamp, J. P., Fontana, M. A., Lee, J. J., Pers, T. H., Rietveld, C. A., Turley, P., Chen, G. B., Emilsson, V., Meddens, S. F. W., Oskarsson, S., Pickrell, J. K., Thom, K., Timshel, P., De Vlaming, R., Abdellaoui, A., Ahluwalia, T. S., Bacelis, J., Baumbach, C., Bjornsdottir, G., Brandsma, J., Pina Concas, M., Derringer, J., Furlotte, N. A., Galesloot, T. E., Girotto, G., Gupta, R., Hall, L. M., Harris, S. E., Hofer, E., Horikoshi, M., Huffman, J. E., Kaasik, K., Kalafati, I. P., Karlsson, R., Kong, A., Lahti, J., Lee, S. J. V. D., DeLeeuw, C., Lind, P. A., Lindgren, K.-.-O., Liu, T., Mangino, M., Marten, J., Mihailov, E., Miller, M. B., Van der Most, P. J., Oldmeadow, C., Payton, A., Pervjakova, N., Peyrot, W. J., Qian, Y., Raitakari, O., Rueedi, R., Salvi, E., Schmidt, B., Schraut, K. E., Shi, J., Smith, A. V., Poot, R. A., St Pourcain, B., Teumer, A., Thorleifsson, G., Verweij, N., Vuckovic, D., Wellmann, J., Westra, H.-.-J., Yang, J., Zhao, W., Zhu, Z., Alizadeh, B. Z., Amin, N., Bakshi, A., Baumeister, S. E., Biino, G., Bønnelykke, K., Boyle, P. A., Campbell, H., Cappuccio, F. P., Davies, G., De Neve, J.-.-E., Deloukas, P., Demuth, I., Ding, J., Eibich, P., Eisele, L., Eklund, N., Evans, D. M., Faul, J. D., Feitosa, M. F., Forstner, A. J., Gandin, I., Gunnarsson, B., Halldórsson, B. V., Harris, T. B., Heath, A. C., Hocking, L. J., Holliday, E. G., Homuth, G., Horan, M. A., Hottenga, J.-.-J., De Jager, P. L., Joshi, P. K., Jugessur, A., Kaakinen, M. A., Kähönen, M., Kanoni, S., Keltigangas-Järvinen, L., Kiemeney, L. A. L. M., Kolcic, I., Koskinen, S., Kraja, A. T., Kroh, M., Kutalik, Z., Latvala, A., Launer, L. J., Lebreton, M. P., Levinson, D. F., Lichtenstein, P., Lichtner, P., Liewald, D. C. M., Cohert Study, L., Loukola, A., Madden, P. A., Mägi, R., Mäki-Opas, T., Marioni, R. E., Marques-Vidal, P., Meddens, G. A., McMahon, G., Meisinger, C., Meitinger, T., Milaneschi, Y., Milani, L., Montgomery, G. W., Myhre, R., Nelson, C. P., Nyholt, D. R., Ollier, W. E. R., Palotie, A., Paternoster, L., Pedersen, N. L., Petrovic, K. E., Porteous, D. J., Räikkönen, K., Ring, S. M., Robino, A., Rostapshova, O., Rudan, I., Rustichini, A., Salomaa, V., Sanders, A. R., Sarin, A.-.-P., Schmidt, H., Scott, R. J., Smith, B. H., Smith, J. A., Staessen, J. A., Steinhagen-Thiessen, E., Strauch, K., Terracciano, A., Tobin, M. D., Ulivi, S., Vaccargiu, S., Quaye, L., Van Rooij, F. J. A., Venturini, C., Vinkhuyzen, A. A. E., Völker, U., Völzke, H., Vonk, J. M., Vozzi, D., Waage, J., Ware, E. B., Willemsen, G., Attia, J. R., Bennett, D. A., Berger, K., Bertram, L., Bisgaard, H., Boomsma, D. I., Borecki, I. B., Bültmann, U., Chabris, C. F., Cucca, F., Cusi, D., Deary, I. J., Dedoussis, G. V., Van Duijn, C. M., Eriksson, J. G., Franke, B., Franke, L., Gasparini, P., Gejman, P. V., Gieger, C., Grabe, H.-.-J., Gratten, J., Groenen, P. J. F., Gudnason, V., Van der Harst, P., Hayward, C., Hinds, D. A., Hoffmann, W., Hyppönen, E., Iacono, W. G., Jacobsson, B., Järvelin, M.-.-R., Jöckel, K.-.-H., Kaprio, J., Kardia, S. L. R., Lehtimäki, T., Lehrer, S. F., Magnusson, P. K. E., Martin, N. G., McGue, M., Metspalu, A., Pendleton, N., Penninx, B. W. J. H., Perola, M., Pirastu, N., Pirastu, M., Polasek, O., Posthuma, D., Power, C., Province, M. A., Samani, N. J., Schlessinger, D., Schmidt, R., Sørensen, T. I. A., Spector, T. D., Stefansson, K., Thorsteinsdottir, U., Thurik, A. R., Timpson, N. J., Tiemeier, H., Tung, J. Y., Uitterlinden, A. G., Vitart, V., Vollenweider, P., Weir, D. R., Wilson, J. F., Wright, A. F., Conley, D. C., Krueger, R. F., Davey Smith, G., Hofman, A., Laibson, D. I., Medland, S. E., Meyer, M. N., Yang, J., Johannesson, M., Visscher, P. M., Esko, T., Koellinger, P. D., Cesarini, D., & Benjamin, D. J. (2016). Genome-wide association study identifies 74 loci associated with educational attainment. Nature, 533, 539-542. doi:10.1038/nature17671.

    Abstract

    Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases
  • Pappa, I., St Pourcain, B., Benke, K., Cavadino, A., Hakulinen, C., Nivard, M. G., Nolte, I. M., Tiesler, C. M. T., Bakermans-Kranenburg, M. J., Davies, G. E., Evans, D. M., Geoffroy, M.-C., Grallert, H., Groen-Blokhuis, M. M., Hudziak, J. J., Kemp, J. P., Keltikangas-Järvinen, L., McMahon, G., Mileva-Seitz, V. R., Motazedi, E. and 23 morePappa, I., St Pourcain, B., Benke, K., Cavadino, A., Hakulinen, C., Nivard, M. G., Nolte, I. M., Tiesler, C. M. T., Bakermans-Kranenburg, M. J., Davies, G. E., Evans, D. M., Geoffroy, M.-C., Grallert, H., Groen-Blokhuis, M. M., Hudziak, J. J., Kemp, J. P., Keltikangas-Järvinen, L., McMahon, G., Mileva-Seitz, V. R., Motazedi, E., Power, C., Raitakari, O. T., Ring, S. M., Rivadeneira, F., Rodriguez, A., Scheet, P. A., Seppälä, I., Snieder, H., Standl, M., Thiering, E., Timpson, N. J., Veenstra, R., Velders, F. P., Whitehouse, A. J. O., Smith, G. D., Heinrich, J., Hypponen, E., Lehtimäki, T., Middeldorp, C. M., Oldehinkel, A. J., Pennell, C. E., Boomsma, D. I., & Tiemeier, H. (2016). A genome-wide approach to children's aggressive behavior: The EAGLE consortium. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 171(5), 562-572. doi:10.1002/ajmg.b.32333.

    Abstract

    Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest sample exploring children's aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children's aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed sample and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10–54%). The meta-analysis of the total sample identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P = 5.30 × 10−8). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning.
  • Robinson, E. B., St Pourcain, B., Anttila, V., Kosmicki, J. A., Bulik-Sullivan, B., Grove, J., Maller, J., Samocha, K. E., Sanders, S. J., Ripke, S., Martin, J., Hollegaard, M. V., Werge, T., Hougaard, D. M., i Psych- S. S. I. Broad Autism Group, Neale, B. M., Evans, D. M., Skuse, D., Mortensen, P. B., Borglum, A. D., Ronald, A. and 2 moreRobinson, E. B., St Pourcain, B., Anttila, V., Kosmicki, J. A., Bulik-Sullivan, B., Grove, J., Maller, J., Samocha, K. E., Sanders, S. J., Ripke, S., Martin, J., Hollegaard, M. V., Werge, T., Hougaard, D. M., i Psych- S. S. I. Broad Autism Group, Neale, B. M., Evans, D. M., Skuse, D., Mortensen, P. B., Borglum, A. D., Ronald, A., Smith, G. D., & Daly, M. J. (2016). Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. Nature Genetics, 48, 552-555. doi:10.1038/ng.3529.

    Abstract

    Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology.

    Additional information

    ng.3529-S1.pdf
  • Stock, N. M., Humphries, K., St Pourcain, B., Bailey, M., Persson, M., Ho, K. M., Ring, S., Marsh, C., Albery, L., Rumsey, N., & Sandy, J. (2016). Opportunities and Challenges in Establishing a Cohort Study: An Example From Cleft Lip/Palate Research in the United Kingdom. Cleft Palate-Craniofacial Journal, (3), 317-325. doi:10.1597/14-306.

    Abstract

    Full text and MPG-specific services(opens in a new window)| Export | Download | Add to List | More... Cleft Palate-Craniofacial Journal Volume 53, Issue 3, May 2016, Pages 317-325 Opportunities and challenges in establishing a cohort study: An example from cleft lip/palate research in the United Kingdom (Article) Stock, N.M.a , Humphries, K.b, St. Pourcain, B.b, Bailey, M.b, Persson, M.a, Ho, K.M.b, Ring, S.b, Marsh, C.c, Albery, L.c, Rumsey, N.a, Sandy, J.b a Centre for Appearance Research, University of the West of England, Coldharbour Lane, Bristol, United Kingdom b Faculty of Medicine and Dentistry, University of Bristol, United Kingdom c South West Cleft Service, University Hospitals Bristol NHS Foundation Trust, United Kingdom Hide additional affiliations View references (32) Abstract Background: Cleft lip and/or palate (CL/P) is one of the most common birth conditions in the world, but little is known about its causes. Professional opinion remains divided as to which treatments may be the most beneficial for patients with CL/P, and the factors that contribute to psychological adjustment are poorly understood. The use of different methodological approaches and tools plays a key role in hampering efforts to address discrepancies within the evidence base. A new UK-wide program of research, The Cleft Collective, was established to combat many of these methodological challenges and to address some of the key research questions important to all CL/P stakeholders. Objective: To describe the establishment of CL/P cohort studies in the United Kingdom and to consider the many opportunities this resource will generate. Results: To date, protocols have been developed and implemented within most UK cleft teams. Biological samples, environmental information, and data pertaining to parental psychological well-being and child development are being collected successfully. Recruitment is currently on track to meet the ambitious target of approximately 9800 individuals from just more than 3000 families. Conclusions: The Cleft Collective cohort studies represent a significant step forward for research in the field of CL/P. The data collected will form a comprehensive resource of information about individuals with CL/P and their families. This resource will provide the basis for many future projects and collaborations, both in the United Kingdom and around the world.
  • van den Berg, S. M., de Moor, M. H. M., Verweij, K. J. H., Krueger, R. F., Luciano, M., Arias Vasquez, A., Matteson, L. K., Derringer, J., Esko, T., Amin, N. F., Gordon, S. D., Hansell, N. K., Hart, A. B., Seppälä, I., Huffman, J. E., Konte, B., Lahti, J., Lee, M., Miller, M., Nutile, T. and 101 morevan den Berg, S. M., de Moor, M. H. M., Verweij, K. J. H., Krueger, R. F., Luciano, M., Arias Vasquez, A., Matteson, L. K., Derringer, J., Esko, T., Amin, N. F., Gordon, S. D., Hansell, N. K., Hart, A. B., Seppälä, I., Huffman, J. E., Konte, B., Lahti, J., Lee, M., Miller, M., Nutile, T., Tanaka, T., Teumer, A., Viktorin, A., Wedenoja, J., Abdellaoui, A., Abecasis, G. R., Adkins, D. E., Agrawal, A., Allik, J., Appel, K., Bigdeli, T. B., Busonero, F., Campbell, H., Costa, P., Smith, G. D., Davies, G., de Wit, H., Ding, J., Engelhardt, B. E., Eriksson, J. G., Fedko, I. O., Ferrucci, L., Franke, B., Giegling, I., Grucza, R., Hartmann, A. M., Heath, A. C., Heinonen, K., Henders, A. K., Homuth, G., Hottenga, J.-J., Iacono, W. G., Janzing, J., Jokela, M., Karlsson, R., Kemp, J., Kirkpatrick, M. G., Latvala, A., Lehtimäki, T., Liewald, D. C., Madden, P. F., Magri, C., Magnusson, P. E., Marten, J., Maschio, A., Mbarek, H., Medland, S. E., Mihailov, E., Milaneschi, Y., Montgomery, G. W., Nauck, M., Nivard, M. G., Ouwens, K. G., Palotie, A., Pettersson, E., Polasek, O., Qian, Y., Pulkki-Råback, L., Raitakari, O., Realo, A., Rose, R. J., Ruggiero, D., Schmidt, C. O., Slutske, W. S., Sorice, R., Starr, J. M., St Pourcain, B., Sutin, A. R., Timpson, N. J., Trochet, H., Vermeulen, S., Vuoksimaa, E., Widen, E., Wouda, J., Wright, M. J., Zgaga, L., Porteous, D., Minelli, A., Palmer, A. A., Rujescu, D., Ciullo, M., Hayward, C., Rudan, I., Metspalu, A., Kaprio, J., Deary, I. J., Räikkönen, K., Wilson, J. F., Keltikangas-Järvinen, L., Bierut, L. J., Hettema, J. M., Grabe, H. J., Penninx, B. W. J. H., van Duijn, C. M., Evans, D. M., Schlessinger, D., Pedersen, N. L., Terracciano, A., McGue, M., Martin, N. G., & Boomsma, D. I. (2016). Meta-analysis of Genome-Wide Association Studies for Extraversion: Findings from the Genetics of Personality Consortium. Behavior Genetics, 46, 170-182. doi:10.1007/s10519-015-9735-5.

    Abstract

    Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion. © 2015 The Author(s)

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  • Genetics of Personality Consortium (2015). Meta-analysis of genome-wide association studies for neuroticism, and the polygenic association with major depressive disorder. JAMA Psychiatry, 72(7), 642-650. doi:10.1001/jamapsychiatry.2015.0554.

    Abstract

    Importance  Neuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63 000 participants (including MDD cases).Objectives To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD.Design, Setting, and Participants Genome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63 661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014.Main Outcomes and Measures Neuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts.Results A genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P = 9.26 × 10−9 in the discovery meta-analysis). This association was not replicated (P = .32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P = 2.38 × 10−8). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09 × 10−12 <} P {<} .05) and MDD (4.02 × 10−9 {<} P {< .05) in the 2 other cohorts.Conclusions and Relevance This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism.

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  • Guggenheim, J. A., St Pourcain, B., McMahon, G., Timpson, N. J., Evans, D. M., & Williams, C. (2015). Assumption-free estimation of the genetic contribution to refractive error across childhood. Molecular Vision, 21, 621-632. Retrieved from http://www.molvis.org/molvis/v21/621.

    Abstract

    Studies in relatives have generally yielded high heritability estimates for refractive error: twins 75–90%, families 15–70%. However, because related individuals often share a common environment, these estimates are inflated (via misallocation of unique/common environment variance). We calculated a lower-bound heritability estimate for refractive error free from such bias. Between the ages 7 and 15 years, participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) underwent non-cycloplegic autorefraction at regular research clinics. At each age, an estimate of the variance in refractive error explained by single nucleotide polymorphism (SNP) genetic variants was calculated using genome-wide complex trait analysis (GCTA) using high-density genome-wide SNP genotype information (minimum N at each age=3,404). The variance in refractive error explained by the SNPs (“SNP heritability”) was stable over childhood: Across age 7–15 years, SNP heritability averaged 0.28 (SE=0.08, p<0.001). The genetic correlation for refractive error between visits varied from 0.77 to 1.00 (all p<0.001) demonstrating that a common set of SNPs was responsible for the genetic contribution to refractive error across this period of childhood. Simulations suggested lack of cycloplegia during autorefraction led to a small underestimation of SNP heritability (adjusted SNP heritability=0.35; SE=0.09). To put these results in context, the variance in refractive error explained (or predicted) by the time participants spent outdoors was <0.005 and by the time spent reading was <0.01, based on a parental questionnaire completed when the child was aged 8–9 years old. Genetic variation captured by common SNPs explained approximately 35% of the variation in refractive error between unrelated subjects. This value sets an upper limit for predicting refractive error using existing SNP genotyping arrays, although higher-density genotyping in larger samples and inclusion of interaction effects is expected to raise this figure toward twin- and family-based heritability estimates. The same SNPs influenced refractive error across much of childhood. Notwithstanding the strong evidence of association between time outdoors and myopia, and time reading and myopia, less than 1% of the variance in myopia at age 15 was explained by crude measures of these two risk factors, indicating that their effects may be limited, at least when averaged over the whole population.
  • St Pourcain, B., Haworth, C. M. A., Davis, O. S. P., Wang, K., Timpson, N. J., Evans, D. M., Kemp, J. P., Ronald, A., Price, T., Meaburn, E., Ring, S. M., Golding, J., Hakonarson, H., Plomin, R., & Davey Smith, G. (2015). Heritability and genome-wide analyses of problematic peer relationships during childhood and adolescence. Human Genetics, 134(6), 539-551. doi:10.1007/s00439-014-1514-5.

    Abstract

    Peer behaviour plays an important role in the development of social adjustment, though little is known about its genetic architecture. We conducted a twin study combined with a genome-wide complex trait analysis (GCTA) and a genome-wide screen to characterise genetic influences on problematic peer behaviour during childhood and adolescence. This included a series of longitudinal measures (parent-reported Strengths-and-Difficulties Questionnaire) from a UK population-based birth-cohort (ALSPAC, 4–17 years), and a UK twin sample (TEDS, 4–11 years). Longitudinal twin analysis (TEDS; N ≤ 7,366 twin pairs) showed that peer problems in childhood are heritable (4–11 years, 0.60 < twin-h 2 ≤ 0.71) but genetically heterogeneous from age to age (4–11 years, twin-r g = 0.30). GCTA (ALSPAC: N ≤ 5,608, TEDS: N ≤ 2,691) provided furthermore little support for the contribution of measured common genetic variants during childhood (4–12 years, 0.02 < GCTA-h 2(Meta) ≤ 0.11) though these influences become stronger in adolescence (13–17 years, 0.14 < GCTA-h 2(ALSPAC) ≤ 0.27). A subsequent cross-sectional genome-wide screen in ALSPAC (N ≤ 6,000) focussed on peer problems with the highest GCTA-heritability (10, 13 and 17 years, 0.0002 < GCTA-P ≤ 0.03). Single variant signals (P ≤ 10−5) were followed up in TEDS (N ≤ 2835, 9 and 11 years) and, in search for autism quantitative trait loci, explored within two autism samples (AGRE: N Pedigrees = 793; ACC: N Cases = 1,453/N Controls = 7,070). There was, however, no evidence for association in TEDS and little evidence for an overlap with the autistic continuum. In summary, our findings suggest that problematic peer relationships are heritable but genetically complex and heterogeneous from age to age, with an increase in common measurable genetic variation during adolescence.
  • Stergiakouli, E., Martin, J., Hamshere, M. L., Langley, K., Evans, D. M., St Pourcain, B., Timpson, N. J., Owen, M. J., O'Donovan, M., Thapar, A., & Davey Smith, G. (2015). Shared Genetic Influences Between Attention-Deficit/Hyperactivity Disorder (ADHD) Traits in Children and Clinical ADHD. Journal of the American Academy of Child and Adolescent Psychiatry, 54(4), 322-327. doi:10.1016/j.jaac.2015.01.010.
  • The UK10K Consortium (2015). The UK10K project identifies rare variants in health and disease. Nature, 526(7571), 82-89. doi:10.1038/nature14962.

    Abstract

    The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.
  • van der Valk, R. J. P., Kreiner-Møller, E., Kooijman, M. N., Guxens, M., Stergiakouli, E., Sääf, A., Bradfield, J. P., Geller, F., Hayes, M. G., Cousminer, D. L., Körner, A., Thiering, E., Curtin, J. A., Myhre, R., Huikari, V., Joro, R., Kerkhof, M., Warrington, N. M., Pitkänen, N., Ntalla, I. and 98 morevan der Valk, R. J. P., Kreiner-Møller, E., Kooijman, M. N., Guxens, M., Stergiakouli, E., Sääf, A., Bradfield, J. P., Geller, F., Hayes, M. G., Cousminer, D. L., Körner, A., Thiering, E., Curtin, J. A., Myhre, R., Huikari, V., Joro, R., Kerkhof, M., Warrington, N. M., Pitkänen, N., Ntalla, I., Horikoshi, M., Veijola, R., Freathy, R. M., Teo, Y.-Y., Barton, S. J., Evans, D. M., Kemp, J. P., St Pourcain, B., Ring, S. M., Davey Smith, G., Bergström, A., Kull, I., Hakonarson, H., Mentch, F. D., Bisgaard, H., Chawes, B., Stokholm, J., Waage, J., Eriksen, P., Sevelsted, A., Melbye, M., van Duijn, C. M., Medina-Gomez, C., Hofman, A., de Jongste, J. C., Taal, H. R., Uitterlinden, A. G., Armstrong, L. L., Eriksson, J., Palotie, A., Bustamante, M., Estivill, X., Gonzalez, J. R., Llop, S., Kiess, W., Mahajan, A., Flexeder, C., Tiesler, C. M. T., Murray, C. S., Simpson, A., Magnus, P., Sengpiel, V., Hartikainen, A.-L., Keinanen-Kiukaanniemi, S., Lewin, A., Da Silva Couto Alves, A., Blakemore, A. I., Buxton, J. L., Kaakinen, M., Rodriguez, A., Sebert, S., Vaarasmaki, M., Lakka, T., Lindi, V., Gehring, U., Postma, D. S., Ang, W., Newnham, J. P., Lyytikäinen, L.-P., Pahkala, K., Raitakari, O. T., Panoutsopoulou, K., Zeggini, E., Boomsma, D. I., Groen-Blokhuis, M., Ilonen, J., Franke, L., Hirschhorn, J. N., Pers, T. H., Liang, L., Huang, J., Hocher, B., Knip, M., Saw, S.-M., Holloway, J. W., Melén, E., Grant, S. F. A., Feenstra, B., Lowe, W. L., Widén, E., Sergeyev, E., Grallert, H., Custovic, A., Jacobsson, B., Jarvelin, M.-R., Atalay, M., Koppelman, G. H., Pennell, C. E., Niinikoski, H., Dedoussis, G. V., Mccarthy, M. I., Frayling, T. M., Sunyer, J., Timpson, N. J., Rivadeneira, F., Bønnelykke, K., Jaddoe, V. W. V., & Early Growth Genetics (EGG) Consortium (2015). A novel common variant in DCST2 is associated with length in early life and height in adulthood. Human Molecular Genetics, 24(4), 1155-1168. doi:10.1093/hmg/ddu510.

    Abstract

    Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
  • Warrington, N. M., Howe, L. D., Paternoster, L., Kaakinen, M., Herrala, S., Huikari, V., Wu, Y. Y., Kemp, J. P., Timpson, N. J., St Pourcain, B., Smith, G. D., Tilling, K., Jarvelin, M.-R., Pennell, C. E., Evans, D. M., Lawlor, D. A., Briollais, L., & Palmer, L. J. (2015). A genome-wide association study of body mass index across early life and childhood. International Journal of Epidemiology, 44(2), 700-712. doi:10.1093/ije/dyv077.

    Abstract

    Background: Several studies have investigated the effect of known adult body mass index (BMI) associated single nucleotide polymorphisms (SNPs) on BMI in childhood. There has been no genome-wide association study (GWAS) of BMI trajectories over childhood. Methods: We conducted a GWAS meta-analysis of BMI trajectories from 1 to 17 years of age in 9377 children (77 967 measurements) from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Western Australian Pregnancy Cohort (Raine) Study. Genome-wide significant loci were examined in a further 3918 individuals (48 530 measurements) from Northern Finland. Linear mixed effects models with smoothing splines were used in each cohort for longitudinal modelling of BMI. Results: A novel SNP, downstream from the FAM120AOS gene on chromosome 9, was detected in the meta-analysis of ALSPAC and Raine. This association was driven by a difference in BMI at 8 years (T allele of rs944990 increased BMI; PSNP = 1.52 × 10−8), with a modest association with change in BMI over time (PWald(Change) = 0.006). Three known adult BMI-associated loci (FTO, MC4R and ADCY3) and one childhood obesity locus (OLFM4) reached genome-wide significance (PWald < 1.13 × 10−8) with BMI at 8 years and/or change over time. Conclusions: This GWAS of BMI trajectories over childhood identified a novel locus that warrants further investigation. We also observed genome-wide significance with previously established obesity loci, making the novel observation that these loci affected both the level and the rate of change in BMI. We have demonstrated that the use of repeated measures data can increase power to allow detection of genetic loci with smaller sample sizes.
  • Warrington, N. M., Zhu, G., Dy, V., Heath, A. C., Madden, P. A. F., Hemani, G., Kemp, J. P., McMahon, G., St Pourcain, B., Timpson, N. J., Taylor, C. M., Golding, J., Lawlor, D. A., Steer, C., Montgomery, G. W., Martin, N. G., Smith, G. D., Evans, D. M., & Whitfield, J. B. (2015). Genome-wide association study of blood lead shows multiple associations near ALAD. Human Molecular Genetics, 24(13), 3871-3879. doi:10.1093/hmg/ddv112.

    Abstract

    Exposure to high levels of environmental lead, or biomarker evidence of high body lead content, is associated with anaemia, developmental and neurological deficits in children, and increased mortality in adults. Adverse effects of lead still occur despite substantial reduction in environmental exposure. There is genetic variation between individuals in blood lead concentration but the polymorphisms contributing to this have not been defined. We measured blood or erythrocyte lead content, and carried out genome-wide association analysis, on population-based cohorts of adult volunteers from Australia and UK (N = 5433). Samples from Australia were collected in two studies, in 1993–1996 and 2002–2005 and from UK in 1991–1992. One locus, at ALAD on chromosome 9, showed consistent association with blood lead across countries and evidence for multiple independent allelic effects. The most significant single nucleotide polymorphism (SNP), rs1805313 (P = 3.91 × 10−14 for lead concentration in a meta-analysis of all data), is known to have effects on ALAD expression in blood cells but other SNPs affecting ALAD expression did not affect blood lead. Variants at 12 other loci, including ABO, showed suggestive associations (5 × 10−6 >} P {> 5 × 10−8). Identification of genetic polymorphisms affecting blood lead reinforces the view that genetic factors, as well as environmental ones, are important in determining blood lead levels. The ways in which ALAD variation affects lead uptake or distribution are still to be determined.
  • Li, Q., Wojciechowski, R., Simpson, C. L., Hysi, P. G., Verhoeven, V. J. M., Ikram, M. K., Höhn, R., Vitart, V., Hewitt, A. W., Oexle, K., Mäkelä, K.-M., MacGregor, S., Pirastu, M., Fan, Q., Cheng, C.-Y., St Pourcain, B., McMahon, G., Kemp, J. P., Northstone, K., Rahi, J. S. and 69 moreLi, Q., Wojciechowski, R., Simpson, C. L., Hysi, P. G., Verhoeven, V. J. M., Ikram, M. K., Höhn, R., Vitart, V., Hewitt, A. W., Oexle, K., Mäkelä, K.-M., MacGregor, S., Pirastu, M., Fan, Q., Cheng, C.-Y., St Pourcain, B., McMahon, G., Kemp, J. P., Northstone, K., Rahi, J. S., Cumberland, P. M., Martin, N. G., Sanfilippo, P. G., Lu, Y., Wang, Y. X., Hayward, C., Polašek, O., Campbell, H., Bencic, G., Wright, A. F., Wedenoja, J., Zeller, T., Schillert, A., Mirshahi, A., Lackner, K., Yip, S. P., Yap, M. K. H., Ried, J. S., Gieger, C., Murgia, F., Wilson, J. F., Fleck, B., Yazar, S., Vingerling, J. R., Hofman, A., Uitterlinden, A., Rivadeneira, F., Amin, N., Karssen, L., Oostra, B. A., Zhou, X., Teo, Y.-Y., Tai, E. S., Vithana, E., Barathi, V., Zheng, Y., Siantar, R. G., Neelam, K., Shin, Y., Lam, J., Yonova-Doing, E., Venturini, C., Hosseini, S. M., Wong, H.-S., Lehtimäki, T., Kähönen, M., Raitakari, O., Timpson, N. J., Evans, D. M., Khor, C.-C., Aung, T., Young, T. L., Mitchell, P., Klein, B., van Duijn, C. M., Meitinger, T., Jonas, J. B., Baird, P. N., Mackey, D. A., Wong, T. Y., Saw, S.-M., Pärssinen, O., Stambolian, D., Hammond, C. J., Klaver, C. C. W., Williams, C., Paterson, A. D., Bailey-Wilson, J. E., & Guggenheim, J. A. (2015). Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium. Human Genetics, 134, 131-146. doi:10.1007/s00439-014-1500-y.

    Abstract

    To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E−8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E−07), TOX (rs7823467, P = 3.47E−07) and LINC00340 (rs12212674, P = 1.49E−06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = −0.59, P = 2.10E−04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
  • Benyamin, B., St Pourcain, B., Davis, O. S., Davies, G., Hansell, N. K., Brion, M.-J., Kirkpatrick, R. M., Cents, R. A. M., Franić, S., Miller, M. B., Haworth, C. M. A., Meaburn, E., Price, T. S., Evans, D. M., Timpson, N., Kemp, J., Ring, S., McArdle, W., Medland, S. E., Yang, J. and 23 moreBenyamin, B., St Pourcain, B., Davis, O. S., Davies, G., Hansell, N. K., Brion, M.-J., Kirkpatrick, R. M., Cents, R. A. M., Franić, S., Miller, M. B., Haworth, C. M. A., Meaburn, E., Price, T. S., Evans, D. M., Timpson, N., Kemp, J., Ring, S., McArdle, W., Medland, S. E., Yang, J., Harris, S. E., Liewald, D. C., Scheet, P., Xiao, X., Hudziak, J. J., de Geus, E. J. C., Jaddoe, V. W. V., Starr, J. M., Verhulst, F. C., Pennell, C., Tiemeier, H., Iacono, W. G., Palmer, L. J., Montgomery, G. W., Martin, N. G., Boomsma, D. I., Posthuma, D., McGue, M., Wright, M. J., Davey Smith, G., Deary, I. J., Plomin, R., & Visscher, P. M. (2014). Childhood intelligence is heritable, highly polygenic and associated with FNBP1L. Molecular Psychiatry, 19(2), 253-258. doi:10.1038/mp.2012.184.

    Abstract

    Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6–18 years) from 17 989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22–46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10−15, 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10−5), 3.5% (P=10−3) and 0.5% (P=6 × 10−5) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.
  • Bolton, J. L., Hayward, C., Direk, N., Lewis, J. G., Hammond, G. L., Hill, L. A., Anderson, A., Huffman, J., Wilson, J. F., Campbell, H., Rudan, I., Wright, A., Hastie, N., Wild, S. H., Velders, F. P., Hofman, A., Uitterlinden, A. G., Lahti, J., Räikkönen, K., Kajantie, E. and 37 moreBolton, J. L., Hayward, C., Direk, N., Lewis, J. G., Hammond, G. L., Hill, L. A., Anderson, A., Huffman, J., Wilson, J. F., Campbell, H., Rudan, I., Wright, A., Hastie, N., Wild, S. H., Velders, F. P., Hofman, A., Uitterlinden, A. G., Lahti, J., Räikkönen, K., Kajantie, E., Widen, E., Palotie, A., Eriksson, J. G., Kaakinen, M., Järvelin, M.-R., Timpson, N. J., Davey Smith, G., Ring, S. M., Evans, D. M., St Pourcain, B., Tanaka, T., Milaneschi, Y., Bandinelli, S., Ferrucci, L., van der Harst, P., Rosmalen, J. G. M., Bakker, S. J. L., Verweij, N., Dullaart, R. P. F., Mahajan, A., Lindgren, C. M., Morris, A., Lind, L., Ingelsson, E., Anderson, L. N., Pennell, C. E., Lye, S. J., Matthews, S. G., Eriksson, J., Mellstrom, D., Ohlsson, C., Price, J. F., Strachan, M. W. J., Reynolds, R. M., Tiemeier, H., Walker, B. R., & CORtisol NETwork (CORNET) Consortium (2014). Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin. PLoS Genetics, 10(7): e1004474. doi:10.1371/journal.pgen.1004474.

    Abstract

    Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
  • Eaves, L. J., St Pourcain, B., Smith, G. D., York, T. P., & Evans, D. M. (2014). Resolving the Effects of Maternal and Offspring Genotype on Dyadic Outcomes in Genome Wide Complex Trait Analysis (“M-GCTA”). Behavior Genetics, 44(5), 445-455. doi:10.1007/s10519-014-9666-6.

    Abstract

    Genome wide complex trait analysis (GCTA) is extended to include environmental effects of the maternal genotype on offspring phenotype (“maternal effects”, M-GCTA). The model includes parameters for the direct effects of the offspring genotype, maternal effects and the covariance between direct and maternal effects. Analysis of simulated data, conducted in OpenMx, confirmed that model parameters could be recovered by full information maximum likelihood (FIML) and evaluated the biases that arise in conventional GCTA when indirect genetic effects are ignored. Estimates derived from FIML in OpenMx showed very close agreement to those obtained by restricted maximum likelihood using the published algorithm for GCTA. The method was also applied to illustrative perinatal phenotypes from ~4,000 mother-offspring pairs from the Avon Longitudinal Study of Parents and Children. The relative merits of extended GCTA in contrast to quantitative genetic approaches based on analyzing the phenotypic covariance structure of kinships are considered.
  • Guggenheim, J. A., Williams, C., Northstone, K., Howe, L. D., Tilling, K., St Pourcain, B., McMahon, G., & Lawlor, D. A. (2014). Does Vitamin D Mediate the Protective Effects of Time Outdoors On Myopia? Findings From a Prospective Birth Cohort. Investigative Ophthalmology & Visual Science, 55(12), 8550-8558. doi:10.1167/iovs.14-15839.
  • Kemp, J. P., Sayers, A., Paternoster, L., Evans, D. M., Deere, K., St Pourcain, B., Timpson, N. J., Ring, S. M., Lorentzon, M., Lehtimäki, T., Eriksson, J., Kähönen, M., Raitakari, O., Laaksonen, M., Sievänen, H., Viikari, J., Lyytikäinen, L.-P., Smith, G. D., Fraser, W. D., Vandenput, L. and 2 moreKemp, J. P., Sayers, A., Paternoster, L., Evans, D. M., Deere, K., St Pourcain, B., Timpson, N. J., Ring, S. M., Lorentzon, M., Lehtimäki, T., Eriksson, J., Kähönen, M., Raitakari, O., Laaksonen, M., Sievänen, H., Viikari, J., Lyytikäinen, L.-P., Smith, G. D., Fraser, W. D., Vandenput, L., Ohlsson, C., & Tobias, J. H. (2014). Does Bone Resorption Stimulate Periosteal Expansion? A Cross-Sectional Analysis of β-C-telopeptides of Type I Collagen (CTX), Genetic Markers of the RANKL Pathway, and Periosteal Circumference as Measured by pQCT. Journal of Bone and Mineral Research, 29(4), 1015-1024. doi:10.1002/jbmr.2093.

    Abstract

    We hypothesized that bone resorption acts to increase bone strength through stimulation of periosteal expansion. Hence, we examined whether bone resorption, as reflected by serum β-C-telopeptides of type I collagen (CTX), is positively associated with periosteal circumference (PC), in contrast to inverse associations with parameters related to bone remodeling such as cortical bone mineral density (BMDC ). CTX and mid-tibial peripheral quantitative computed tomography (pQCT) scans were available in 1130 adolescents (mean age 15.5 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Analyses were adjusted for age, gender, time of sampling, tanner stage, lean mass, fat mass, and height. CTX was positively related to PC (β=0.19 [0.13, 0.24]) (coefficient=SD change per SD increase in CTX, 95% confidence interval)] but inversely associated with BMDC (β=-0.46 [-0.52,-0.40]) and cortical thickness [β=-0.11 (-0.18, -0.03)]. CTX was positively related to bone strength as reflected by the strength-strain index (SSI) (β=0.09 [0.03, 0.14]). To examine the causal nature of this relationship, we then analyzed whether single-nucleotide polymorphisms (SNPs) within key osteoclast regulatory genes, known to reduce areal/cortical BMD, conversely increase PC. Fifteen such genetic variants within or proximal to genes encoding receptor activator of NF-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) were identified by literature search. Six of the 15 alleles that were inversely related to BMD were positively related to CTX (p<}0.05 cut-off) (n=2379). Subsequently, we performed a meta-analysis of associations between these SNPs and PC in ALSPAC (n=3382), Gothenburg Osteoporosis and Obesity Determinants (GOOD) (n=938), and the Young Finns Study (YFS) (n=1558). Five of the 15 alleles that were inversely related to BMD were positively related to PC (p{<0.05 cut-off). We conclude that despite having lower BMD, individuals with a genetic predisposition to higher bone resorption have greater bone size, suggesting that higher bone resorption is permissive for greater periosteal expansion.
  • Kemp, J. P., Medina-Gomez, C., Estrada, K., St Pourcain, B., Heppe, D. H. M., Warrington, N. M., Oei, L., Ring, S. M., Kruithof, C. J., Timpson, N. J., Wolber, L. E., Reppe, S., Gautvik, K., Grundberg, E., Ge, B., van der Eerden, B., van de Peppel, J., Hibbs, M. A., Ackert-Bicknell, C. L., Choi, K. and 13 moreKemp, J. P., Medina-Gomez, C., Estrada, K., St Pourcain, B., Heppe, D. H. M., Warrington, N. M., Oei, L., Ring, S. M., Kruithof, C. J., Timpson, N. J., Wolber, L. E., Reppe, S., Gautvik, K., Grundberg, E., Ge, B., van der Eerden, B., van de Peppel, J., Hibbs, M. A., Ackert-Bicknell, C. L., Choi, K., Koller, D. L., Econs, M. J., Williams, F. M. K., Foroud, T., Zillikens, M. C., Ohlsson, C., Hofman, A., Uitterlinden, A. G., Davey Smith, G., Jaddoe, V. W. V., Tobias, J. H., Rivadeneira, F., & Evans, D. M. (2014). Phenotypic dissection of bone mineral density reveals skeletal site specificity and facilitates the identification of novel loci in the genetic regulation of bone mass attainment. PLoS Genetics, 10(6): e1004423. doi:10.1371/journal.pgen.1004423.

    Abstract

    Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ∼ 4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (r(e) = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (r(e) = 0.20-0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n ∼ 9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01 × 10(-37)), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31 × 10(-14)). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4 × 10(-10)). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.
  • St Pourcain, B., Cents, R. A., Whitehouse, A. J., Haworth, C. M., Davis, O. S., O’Reilly, P. F., Roulstone, S., Wren, Y., Ang, Q. W., Velders, F. P., Evans, D. M., Kemp, J. P., Warrington, N. M., Miller, L., Timpson, N. J., Ring, S. M., Verhulst, F. C., Hofman, A., Rivadeneira, F., Meaburn, E. L. and 12 moreSt Pourcain, B., Cents, R. A., Whitehouse, A. J., Haworth, C. M., Davis, O. S., O’Reilly, P. F., Roulstone, S., Wren, Y., Ang, Q. W., Velders, F. P., Evans, D. M., Kemp, J. P., Warrington, N. M., Miller, L., Timpson, N. J., Ring, S. M., Verhulst, F. C., Hofman, A., Rivadeneira, F., Meaburn, E. L., Price, T. S., Dale, P. S., Pillas, D., Yliherva, A., Rodriguez, A., Golding, J., Jaddoe, V. W., Jarvelin, M.-R., Plomin, R., Pennell, C. E., Tiemeier, H., & Davey Smith, G. (2014). Common variation near ROBO2 is associated with expressive vocabulary in infancy. Nature Communications, 5: 4831. doi:10.1038/ncomms5831.
  • St Pourcain, B., Skuse, D. H., Mandy, W. P., Wang, K., Hakonarson, H., Timpson, N. J., Evans, D. M., Kemp, J. P., Ring, S. M., McArdle, W. L., Golding, J., & Smith, G. D. (2014). Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence. Molecular Autism, 5: 18. doi:10.1186/2040-2392-5-18.

    Abstract

    Background Social-communication abilities are heritable traits, and their impairments overlap with the autism continuum. To characterise the genetic architecture of social-communication difficulties developmentally and identify genetic links with the autistic dimension, we conducted a genome-wide screen of social-communication problems at multiple time-points during childhood and adolescence. Methods Social-communication difficulties were ascertained at ages 8, 11, 14 and 17 years in a UK population-based birth cohort (Avon Longitudinal Study of Parents and Children; N ≤ 5,628) using mother-reported Social Communication Disorder Checklist scores. Genome-wide Complex Trait Analysis (GCTA) was conducted for all phenotypes. The time-points with the highest GCTA heritability were subsequently analysed for single SNP association genome-wide. Type I error in the presence of measurement relatedness and the likelihood of observing SNP signals near known autism susceptibility loci (co-location) were assessed via large-scale, genome-wide permutations. Association signals (P ≤ 10−5) were also followed up in Autism Genetic Resource Exchange pedigrees (N = 793) and the Autism Case Control cohort (Ncases/Ncontrols = 1,204/6,491). Results GCTA heritability was strongest in childhood (h2(8 years) = 0.24) and especially in later adolescence (h2(17 years) = 0.45), with a marked drop during early to middle adolescence (h2(11 years) = 0.16 and h2(14 years) = 0.08). Genome-wide screens at ages 8 and 17 years identified for the latter time-point evidence for association at 3p22.2 near SCN11A (rs4453791, P = 9.3 × 10−9; genome-wide empirical P = 0.011) and suggestive evidence at 20p12.3 at PLCB1 (rs3761168, P = 7.9 × 10−8; genome-wide empirical P = 0.085). None of these signals contributed to risk for autism. However, the co-location of population-based signals and autism susceptibility loci harbouring rare mutations, such as PLCB1, is unlikely to be due to chance (genome-wide empirical Pco-location = 0.007). Conclusions Our findings suggest that measurable common genetic effects for social-communication difficulties vary developmentally and that these changes may affect detectable overlaps with the autism spectrum.

    Additional information

    13229_2013_113_MOESM1_ESM.docx
  • Stergiakouli, E., Gaillard, R., Tavaré, J. M., Balthasar, N., Loos, R. J., Taal, H. R., Evans, D. M., Rivadeneira, F., St Pourcain, B., Uitterlinden, A. G., Kemp, J. P., Hofman, A., Ring, S. M., Cole, T. J., Jaddoe, V. W. V., Davey Smith, G., & Timpson, N. J. (2014). Genome-wide association study of height-adjusted BMI in childhood identifies functional variant in ADCY3. Obesity, 22(10), 2252-2259. doi:10.1002/oby.20840.

    Abstract

    OBJECTIVE: Genome-wide association studies (GWAS) of BMI are mostly undertaken under the assumption that "kg/m(2) " is an index of weight fully adjusted for height, but in general this is not true. The aim here was to assess the contribution of common genetic variation to a adjusted version of that phenotype which appropriately accounts for covariation in height in children. METHODS: A GWAS of height-adjusted BMI (BMI[x] = weight/height(x) ), calculated to be uncorrelated with height, in 5809 participants (mean age 9.9 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC) was performed. RESULTS: GWAS based on BMI[x] yielded marked differences in genomewide results profile. SNPs in ADCY3 (adenylate cyclase 3) were associated at genome-wide significance level (rs11676272 (0.28 kg/m(3.1) change per allele G (0.19, 0.38), P = 6 × 10(-9) ). In contrast, they showed marginal evidence of association with conventional BMI [rs11676272 (0.25 kg/m(2) (0.15, 0.35), P = 6 × 10(-7) )]. Results were replicated in an independent sample, the Generation R study. CONCLUSIONS: Analysis of BMI[x] showed differences to that of conventional BMI. The association signal at ADCY3 appeared to be driven by a missense variant and it was strongly correlated with expression of this gene. Our work highlights the importance of well understood phenotype use (and the danger of convention) in characterising genetic contributions to complex traits.

    Additional information

    oby20840-sup-0001-suppinfo.docx
  • Ward, M. E., McMahon, G., St Pourcain, B., Evans, D. M., Rietveld, C. A., Benjamin, D. J., Koellinger, P. D., Cesarini, D., Smith, G. D., Timpson, N. J., & Consortium}, {. S. G. A. (2014). Genetic variation associated with differential educational attainment in adults has anticipated associations with school performance in children. PLoS ONE, 9(7): e100248. doi:10.1371/journal.pone.0100248.

    Abstract

    Genome-wide association study results have yielded evidence for the association of common genetic variants with crude measures of completed educational attainment in adults. Whilst informative, these results do not inform as to the mechanism of these effects or their presence at earlier ages and where educational performance is more routinely and more precisely assessed. Single nucleotide polymorphisms exhibiting genome-wide significant associations with adult educational attainment were combined to derive an unweighted allele score in 5,979 and 6,145 young participants from the Avon Longitudinal Study of Parents and Children with key stage 3 national curriculum test results (SATS results) available at age 13 to 14 years in English and mathematics respectively. Standardised (z-scored) results for English and mathematics showed an expected relationship with sex, with girls exhibiting an advantage over boys in English (0.433 SD (95%CI 0.395, 0.470), p<10-10) with more similar results (though in the opposite direction) in mathematics (0.042 SD (95%CI 0.004, 0.080), p = 0.030). Each additional adult educational attainment increasing allele was associated with 0.041 SD (95%CI 0.020, 0.063), p = 1.79×10-04 and 0.028 SD (95%CI 0.007, 0.050), p = 0.01 increases in standardised SATS score for English and mathematics respectively. Educational attainment is a complex multifactorial behavioural trait which has not had heritable contributions to it fully characterised. We were able to apply the results from a large study of adult educational attainment to a study of child exam performance marking events in the process of learning rather than realised adult end product. Our results support evidence for common, small genetic contributions to educational attainment, but also emphasise the likely lifecourse nature of this genetic effect. Results here also, by an alternative route, suggest that existing methods for child examination are able to recognise early life variation likely to be related to ultimate educational attainment.
  • Bønnelykke, K., Matheson, M. C., Pers, T. H., Granell, R., Strachan, D. P., Alves, A. C., Linneberg, A., Curtin, J. A., Warrington, N. M., Standl, M., Kerkhof, M., Jonsdottir, I., Bukvic, B. K., Kaakinen, M., Sleimann, P., Thorleifsson, G., Thorsteinsdottir, U., Schramm, K., Baltic, S., Kreiner-Møller, E. and 47 moreBønnelykke, K., Matheson, M. C., Pers, T. H., Granell, R., Strachan, D. P., Alves, A. C., Linneberg, A., Curtin, J. A., Warrington, N. M., Standl, M., Kerkhof, M., Jonsdottir, I., Bukvic, B. K., Kaakinen, M., Sleimann, P., Thorleifsson, G., Thorsteinsdottir, U., Schramm, K., Baltic, S., Kreiner-Møller, E., Simpson, A., St Pourcain, B., Coin, L., Hui, J., Walters, E. H., Tiesler, C. M. T., Duffy, D. L., Jones, G., Ring, S. M., McArdle, W. L., Price, L., Robertson, C. F., Pekkanen, J., Tang, C. S., Thiering, E., Montgomery, G. W., Hartikainen, A.-L., Dharmage, S. C., Husemoen, L. L., Herder, C., Kemp, J. P., Elliot, P., James, A., Waldenberger, M., Abramson, M. J., Fairfax, B. P., Knight, J. C., Gupta, R., Thompson, P. J., Holt, P., Sly, P., Hirschhorn, J. N., Blekic, M., Weidinger, S., Hakonarsson, H., Stefansson, K., Heinrich, J., Postma, D. S., Custovic, A., Pennell, C. E., Jarvelin, M.-R., Koppelman, G. H., Timpson, N., Ferreira, M. A., Bisgaard, H., Henderson, A. J., Australian Asthma Genetics Consortium (AAGC), & EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium (2013). Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization. Nature Genetics, 45(8), 902-906. doi:10.1038/ng.2694.

    Abstract

    Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.
  • Brandler, W. M., Morris, A. P., Evans, D. M., Scerri, T. S., Kemp, J. P., Timpson, N. J., St Pourcain, B., Davey Smith, G., Ring, S. M., Stein, J., Monaco, A. P., Talcott, J. B., Fisher, S. E., Webber, C., & Paracchini, S. (2013). Common variants in left/right asymmetry genes and pathways are associated with relative hand skill. PLoS Genetics, 9(9): e1003751. doi:10.1371/journal.pgen.1003751.

    Abstract

    Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728). The most strongly associated variant, rs7182874 (P = 8.68×10−9), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR≤5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR≤5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development.
  • Cousminer, D. L., Berry, D. J., Timpson, N. J., Ang, W., Thiering, E., Byrne, E. M., Taal, H. R., Huikari, V., Bradfield, J. P., Kerkhof, M., Groen-Blokhuis, M. M., Kreiner-Møller, E., Marinelli, M., Holst, C., Leinonen, J. T., Perry, J. R. B., Surakka, I., Pietiläinen, O., Kettunen, J., Anttila, V. and 50 moreCousminer, D. L., Berry, D. J., Timpson, N. J., Ang, W., Thiering, E., Byrne, E. M., Taal, H. R., Huikari, V., Bradfield, J. P., Kerkhof, M., Groen-Blokhuis, M. M., Kreiner-Møller, E., Marinelli, M., Holst, C., Leinonen, J. T., Perry, J. R. B., Surakka, I., Pietiläinen, O., Kettunen, J., Anttila, V., Kaakinen, M., Sovio, U., Pouta, A., Das, S., Lagou, V., Power, C., Prokopenko, I., Evans, D. M., Kemp, J. P., St Pourcain, B., Ring, S., Palotie, A., Kajantie, E., Osmond, C., Lehtimäki, T., Viikari, J. S., Kähönen, M., Warrington, N. M., Lye, S. J., Palmer, L. J., Tiesler, C. M. T., Flexeder, C., Montgomery, G. W., Medland, S. E., Hofman, A., Hakonarson, H., Guxens, M., Bartels, M., Salomaa, V., Murabito, J. M., Kaprio, J., Sørensen, T. I. A., Ballester, F., Bisgaard, H., Boomsma, D. I., Koppelman, G. H., Grant, S. F. A., Jaddoe, V. W. V., Martin, N. G., Heinrich, J., Pennell, C. E., Raitakari, O. T., Eriksson, J. G., Smith, G. D., Hyppönen, E., Järvelin, M.-R., McCarthy, M. I., Ripatti, S., Widén, E., Consortium ReproGen, & Consortium Early Growth Genetics (EGG) (2013). Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity. Human Molecular Genetics, 22(13), 2735-2747. doi:10.1093/hmg/ddt104.

    Abstract

    The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.
  • den Hoed, M., Eijgelsheim, M., Esko, T., Brundel, B. J. J. M., Peal, D. S., Evans, D. M., Nolte, I. M., Segrè, A. V., Holm, H., Handsaker, R. E., Westra, H.-J., Johnson, T., Isaacs, A., Yang, J., Lundby, A., Zhao, J. H., Kim, Y. J., Go, M. J., Almgren, P., Bochud, M. and 249 moreden Hoed, M., Eijgelsheim, M., Esko, T., Brundel, B. J. J. M., Peal, D. S., Evans, D. M., Nolte, I. M., Segrè, A. V., Holm, H., Handsaker, R. E., Westra, H.-J., Johnson, T., Isaacs, A., Yang, J., Lundby, A., Zhao, J. H., Kim, Y. J., Go, M. J., Almgren, P., Bochud, M., Boucher, G., Cornelis, M. C., Gudbjartsson, D., Hadley, D., van der Harst, P., Hayward, C., den Heijer, M., Igl, W., Jackson, A. U., Kutalik, Z., Luan, J., Kemp, J. P., Kristiansson, K., Ladenvall, C., Lorentzon, M., Montasser, M. E., Njajou, O. T., O'Reilly, P. F., Padmanabhan, S., St Pourcain, B., Rankinen, T., Salo, P., Tanaka, T., Timpson, N. J., Vitart, V., Waite, L., Wheeler, W., Zhang, W., Draisma, H. H. M., Feitosa, M. F., Kerr, K. F., Lind, P. A., Mihailov, E., Onland-Moret, N. C., Song, C., Weedon, M. N., Xie, W., Yengo, L., Absher, D., Albert, C. M., Alonso, A., Arking, D. E., de Bakker, P. I. W., Balkau, B., Barlassina, C., Benaglio, P., Bis, J. C., Bouatia-Naji, N., Brage, S., Chanock, S. J., Chines, P. S., Chung, M., Darbar, D., Dina, C., Dörr, M., Elliott, P., Felix, S. B., Fischer, K., Fuchsberger, C., de Geus, E. J. C., Goyette, P., Gudnason, V., Harris, T. B., Hartikainen, A.-L., Havulinna, A. S., Heckbert, S. R., Hicks, A. A., Hofman, A., Holewijn, S., Hoogstra-Berends, F., Hottenga, J.-J., Jensen, M. K., Johansson, A., Junttila, J., Kääb, S., Kanon, B., Ketkar, S., Khaw, K.-T., Knowles, J. W., Kooner, A. S., Kors, J. A., Kumari, M., Milani, L., Laiho, P., Lakatta, E. G., Langenberg, C., Leusink, M., Liu, Y., Luben, R. N., Lunetta, K. L., Lynch, S. N., Markus, M. R. P., Marques-Vidal, P., Mateo Leach, I., McArdle, W. L., McCarroll, S. A., Medland, S. E., Miller, K. A., Montgomery, G. W., Morrison, A. C., Müller-Nurasyid, M., Navarro, P., Nelis, M., O'Connell, J. R., O'Donnell, C. J., Ong, K. K., Newman, A. B., Peters, A., Polasek, O., Pouta, A., Pramstaller, P. P., Psaty, B. M., Rao, D. C., Ring, S. M., Rossin, E. J., Rudan, D., Sanna, S., Scott, R. A., Sehmi, J. S., Sharp, S., Shin, J. T., Singleton, A. B., Smith, A. V., Soranzo, N., Spector, T. D., Stewart, C., Stringham, H. M., Tarasov, K. V., Uitterlinden, A. G., Vandenput, L., Hwang, S.-J., Whitfield, J. B., Wijmenga, C., Wild, S. H., Willemsen, G., Wilson, J. F., Witteman, J. C. M., Wong, A., Wong, Q., Jamshidi, Y., Zitting, P., Boer, J. M. A., Boomsma, D. I., Borecki, I. B., van Duijn, C. M., Ekelund, U., Forouhi, N. G., Froguel, P., Hingorani, A., Ingelsson, E., Kivimaki, M., Kronmal, R. A., Kuh, D., Lind, L., Martin, N. G., Oostra, B. A., Pedersen, N. L., Quertermous, T., Rotter, J. I., van der Schouw, Y. T., Verschuren, W. M. M., Walker, M., Albanes, D., Arnar, D. O., Assimes, T. L., Bandinelli, S., Boehnke, M., de Boer, R. A., Bouchard, C., Caulfield, W. L. M., Chambers, J. C., Curhan, G., Cusi, D., Eriksson, J., Ferrucci, L., van Gilst, W. H., Glorioso, N., de Graaf, J., Groop, L., Gyllensten, U., Hsueh, W.-C., Hu, F. B., Huikuri, H. V., Hunter, D. J., Iribarren, C., Isomaa, B., Jarvelin, M.-R., Jula, A., Kähönen, M., Kiemeney, L. A., van der Klauw, M. M., Kooner, J. S., Kraft, P., Iacoviello, L., Lehtimäki, T., Lokki, M.-L.-L., Mitchell, B. D., Navis, G., Nieminen, M. S., Ohlsson, C., Poulter, N. R., Qi, L., Raitakari, O. T., Rimm, E. B., Rioux, J. D., Rizzi, F., Rudan, I., Salomaa, V., Sever, P. S., Shields, D. C., Shuldiner, A. R., Sinisalo, J., Stanton, A. V., Stolk, R. P., Strachan, D. P., Tardif, J.-C., Thorsteinsdottir, U., Tuomilehto, J., van Veldhuisen, D. J., Virtamo, J., Viikari, J., Vollenweider, P., Waeber, G., Widen, E., Cho, Y. S., Olsen, J. V., Visscher, P. M., Willer, C., Franke, L., Erdmann, J., Thompson, J. R., Pfeufer, A., Sotoodehnia, N., Newton-Cheh, C., Ellinor, P. T., Stricker, B. H. C., Metspalu, A., Perola, M., Beckmann, J. S., Smith, G. D., Stefansson, K., Wareham, N. J., Munroe, P. B., Sibon, O. C. M., Milan, D. J., Snieder, H., Samani, N. J., Loos, R. J. F., Global BPgen Consortium, CARDIoGRAM Consortium, PR GWAS Consortium, QRS GWAS Consortium, QT-IGC Consortium, & CHARGE-AF Consortium (2013). Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nature Genetics, 45(6), 621-631. doi:10.1038/ng.2610.

    Abstract

    Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
  • Eicher, J. D., Powers, N. R., Miller, L. L., Akshoomoff, N., Amaral, D. G., Bloss, C. S., Libiger, O., Schork, N. J., Darst, B. F., Casey, B. J., Chang, L., Ernst, T., Frazier, J., Kaufmann, W. E., Keating, B., Kenet, T., Kennedy, D., Mostofsky, S., Murray, S. S., Sowell, E. R. and 11 moreEicher, J. D., Powers, N. R., Miller, L. L., Akshoomoff, N., Amaral, D. G., Bloss, C. S., Libiger, O., Schork, N. J., Darst, B. F., Casey, B. J., Chang, L., Ernst, T., Frazier, J., Kaufmann, W. E., Keating, B., Kenet, T., Kennedy, D., Mostofsky, S., Murray, S. S., Sowell, E. R., Bartsch, H., Kuperman, J. M., Brown, T. T., Hagler, D. J., Dale, A. M., Jernigan, T. L., St Pourcain, B., Davey Smith, G., Ring, S. M., Gruen, J. R., & Pediatric Imaging, Neurocognition, and Genetics Study (2013). Genome-wide association study of shared components of reading disability and language impairment. Genes, Brain and Behavior, 12(8), 792-801. doi:10.1111/gbb.12085.

    Abstract

    Written and verbal languages are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits-specifically reading disability (RD) and language impairment (LI)-are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome-wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR = 1.81, P = 5.45 × 10(-7) ) and COL4A2 (OR = 1.71, P = 7.59 × 10(-7) ). Markers within NDST4 showed the strongest associations with LI individually (OR = 1.827, P = 1.40 × 10(-7) ). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (P = 0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language.
  • Evans, D. M., Zhu, G., Dy, V., Heath, A. C., Madden, P. A. F., Kemp, J. P., McMahon, G., St Pourcain, B., Timpson, N. J., Golding, J., Lawlor, D. A., Steer, C., Montgomery, G. W., Martin, N. G., Smith, G. D., & Whitfield, J. B. (2013). Genome-wide association study identifies loci affecting blood copper, selenium and zinc. Human Molecular Genetics, 22(19), 3998-4006. doi:10.1093/hmg/ddt239.

    Abstract

    Genetic variation affecting absorption, distribution or excretion of essential trace elements may lead to health effects related to sub-clinical deficiency. We have tested for allelic effects of single-nucleotide polymorphisms (SNPs) on blood copper, selenium and zinc in a genome-wide association study using two adult cohorts from Australia and the UK. Participants were recruited in Australia from twins and their families and in the UK from pregnant women. We measured erythrocyte Cu, Se and Zn (Australian samples) or whole blood Se (UK samples) using inductively coupled plasma mass spectrometry. Genotyping was performed with Illumina chips and > 2.5 m SNPs were imputed from HapMap data. Genome-wide significant associations were found for each element. For Cu, there were two loci on chromosome 1 (most significant SNPs rs1175550, P = 5.03 × 10(-10), and rs2769264, P = 2.63 × 10(-20)); for Se, a locus on chromosome 5 was significant in both cohorts (combined P = 9.40 × 10(-28) at rs921943); and for Zn three loci on chromosomes 8, 15 and X showed significant results (rs1532423, P = 6.40 × 10(-12); rs2120019, P = 1.55 × 10(-18); and rs4826508, P = 1.40 × 10(-12), respectively). The Se locus covers three genes involved in metabolism of sulphur-containing amino acids and potentially of the analogous Se compounds; the chromosome 8 locus for Zn contains multiple genes for the Zn-containing enzyme carbonic anhydrase. Where potentially relevant genes were identified, they relate to metabolism of the element (Se) or to the presence at high concentration of a metal-containing protein (Cu).
  • Evans, D. M., Brion, M. J. A., Paternoster, L., Kemp, J. P., McMahon, G., Munafò, M., Whitfield, J. B., Medland, S. E., Montgomery, G. W., Timpson, N. J., St Pourcain, B., Lawlor, D. A., Martin, N. G., Dehghan, A., Hirschhorn, J., Davey Smith, G., The GIANT consortium, The CRP consortium, & The TAG Consortium (2013). Mining the Human Phenome Using Allelic Scores That Index Biological Intermediates. PLoS Genet, 9(10): e1003919. doi:10.1371/journal.pgen.1003919.

    Abstract

    Author SummaryThe standard approach in genome-wide association studies is to analyse the relationship between genetic variants and disease one marker at a time. Significant associations between markers and disease are then used as evidence to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically only explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates than single markers, and then use these scores to data mine genome-wide association studies. We show how allelic scores derived from known variants as well as allelic scores derived from hundreds of thousands of genetic markers across the genome explain significant portions of the variance in body mass index, levels of C-reactive protein, and LDLc cholesterol, and many of these scores show expected correlations with disease. Power calculations confirm the feasibility of scaling our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. Our method represents a simple way in which tens of thousands of molecular phenotypes could be screened for potential causal relationships with disease.
  • Fatemifar, G., Hoggart, C. J., Paternoster, L., Kemp, J. P., Prokopenko, I., Horikoshi, M., Wright, V. J., Tobias, J. H., Richmond, S., Zhurov, A. I., Toma, A. M., Pouta, A., Taanila, A., Sipila, K., Lähdesmäki, R., Pillas, D., Geller, F., Feenstra, B., Melbye, M., Nohr, E. A. and 6 moreFatemifar, G., Hoggart, C. J., Paternoster, L., Kemp, J. P., Prokopenko, I., Horikoshi, M., Wright, V. J., Tobias, J. H., Richmond, S., Zhurov, A. I., Toma, A. M., Pouta, A., Taanila, A., Sipila, K., Lähdesmäki, R., Pillas, D., Geller, F., Feenstra, B., Melbye, M., Nohr, E. A., Ring, S. M., St Pourcain, B., Timpson, N. J., Davey Smith, G., Jarvelin, M.-R., & Evans, D. M. (2013). Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances. Human Molecular Genetics, 22(18), 3807-3817. doi:10.1093/hmg/ddt231.

    Abstract

    Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption, we performed a population-based genome-wide association study of 'age at first tooth' and 'number of teeth' using 5998 and 6609 individuals, respectively, from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2 446 724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of 15 independent loci, with 10 loci reaching genome-wide significance (P < 5 × 10(-8)) for 'age at first tooth' and 11 loci for 'number of teeth'. Together, these associations explain 6.06% of the variation in 'age of first tooth' and 4.76% of the variation in 'number of teeth'. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including an SNP in the protein-coding region of BMP4 (rs17563, P = 9.080 × 10(-17)). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.
  • Hinds, D. A., McMahon, G., Kiefer, A. K., Do, C. B., Eriksson, N., Evans, D. M., St Pourcain, B., Ring, S. M., Mountain, J. L., Francke, U., Davey-Smith, G., Timpson, N. J., & Tung, J. Y. (2013). A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci. Nat Genet, 45(8), 907-911. doi:10.1038/ng.2686.

    Abstract

    Allergic disease is very common and carries substantial public-health burdens. We conducted a meta-analysis of genome-wide associations with self-reported cat, dust-mite and pollen allergies in 53,862 individuals. We used generalized estimating equations to model shared and allergy-specific genetic effects. We identified 16 shared susceptibility loci with association P<5×10(-8), including 8 loci previously associated with asthma, as well as 4p14 near TLR1, TLR6 and TLR10 (rs2101521, P=5.3×10(-21)); 6p21.33 near HLA-C and MICA (rs9266772, P=3.2×10(-12)); 5p13.1 near PTGER4 (rs7720838, P=8.2×10(-11)); 2q33.1 in PLCL1 (rs10497813, P=6.1×10(-10)), 3q28 in LPP (rs9860547, P=1.2×10(-9)); 20q13.2 in NFATC2 (rs6021270, P=6.9×10(-9)), 4q27 in ADAD1 (rs17388568, P=3.9×10(-8)); and 14q21.1 near FOXA1 and TTC6 (rs1998359, P=4.8×10(-8)). We identified one locus with substantial evidence of differences in effects across allergies at 6p21.32 in the class II human leukocyte antigen (HLA) region (rs17533090, P=1.7×10(-12)), which was strongly associated with cat allergy. Our study sheds new light on the shared etiology of immune and autoimmune disease.
  • Julvez, J., Smith, G. D., Golding, J., Ring, S., St Pourcain, B., Gonzalez, J. R., & Grandjean, P. (2013). Prenatal methylmercury exposure and genetic predisposition to cognitive deficit at age 8 years. Epidemiology, 24(5), 643-650. doi:10.1097/EDE.0b013e31829d5c93.

    Abstract

    BACKGROUND: Cognitive consequences at school age associated with prenatal methylmercury (MeHg) exposure may need to take into account nutritional and sociodemographic cofactors as well as relevant genetic polymorphisms. METHODS: A subsample (n = 1,311) of the Avon Longitudinal Study of Parents and Children (Bristol, UK) was selected, and mercury (Hg) concentrations were measured in freeze-dried umbilical cord tissue as a measure of MeHg exposure. A total of 1135 children had available data on 247 single-nucleotide polymorphisms (SNPs) within relevant genes, as well as the Wechsler Intelligence Scale for Children Intelligence Quotient (IQ) scores at age 8 years. Multivariate regression models were used to assess the associations between MeHg exposure and IQ and to determine possible gene-environment interactions. RESULTS: Hg concentrations indicated low background exposures (mean = 26 ng/g, standard deviation = 13). Log10-transformed Hg was positively associated with IQ, which attenuated after adjustment for nutritional and sociodemographic cofactors. In stratified analyses, a reverse association was found in higher social class families (for performance IQ, P value for interaction = 0.0013) among whom there was a wider range of MeHg exposure. Among 40 SNPs showing nominally significant main effects, MeHg interactions were detected for rs662 (paraoxonase 1) and rs1042838 (progesterone receptor) (P <} 0.05) and for rs3811647 (transferrin) and rs2049046 (brain-derived neurotrophic factor) (P {< 0.10). CONCLUSIONS: In this population with a low level of MeHg exposure, there were only equivocal associations between MeHg exposure and adverse neuropsychological outcomes. Heterogeneities in several relevant genes suggest possible genetic predisposition to MeHg neurotoxicity in a substantial proportion of the population. Future studies need to address this possibility.
  • Mandy, W., Skuse, D., Steer, C., St Pourcain, B., & Oliver, B. R. (2013). Oppositionality and Socioemotional Competence: Interacting Risk Factors in the Development of Childhood Conduct Disorder Symptoms. Journal of the American Academy of Child & Adolescent Psychiatry, 52(7), 718-727. doi:10.1016/j.jaac.2013.04.011.

    Abstract

    Objectives Oppositional behavior in childhood is a probabilistic risk factor for the subsequent development of more serious conduct problems characteristic of conduct disorder (CD). The capacity to understand the subjective states of others (socioemotional competence) helps regulate antisocial behavior in typical development. We hypothesized that socioemotional competence moderates the developmental relationship between oppositionality and CD symptoms, such that oppositional defiant disorder (ODD) symptoms pose the greatest risk for subsequent CD symptoms in children with poor socioemotional competence. Method Parent-report data were collected for 6,218 children at 7 and 10 years of age. Bootstrap multiple regression predicting CD symptoms at age 10 was used to test for an interaction between socioemotional competence and ODD symptoms, while also accounting for direct effects and controlling for sex, maternal education, attention-deficit/hyperactivity disorder symptoms, and CD symptoms at 7 years. We further tested whether the interaction applied to both males and females, and to both aggressive and rule-breaking CD symptoms. Results A significant interaction was found between ODD and socioemotional competence: the association between oppositionality at 7 years and CD traits at 10 years was strongest for children with poor socioemotional capacities. As predicted, this moderation effect was significant in a model predicting aggression, but it was not significant for rule-breaking CD symptoms. Conclusion Socioemotional competence moderates the developmental relationship between mid-childhood oppositionality and more serious conduct problems in later childhood. A capacity to understand the subjective states of others may buffer the risk posed by oppositionality for later CD symptoms, including aggression.
  • St Pourcain, B., Whitehouse, A. J. O., Ang, W. Q., Warrington, N. M., Glessner, J. T., Wang, K., Timpson, N. J., Evans, D. M., Kemp, J. P., Ring, S. M., McArdle, W. L., Golding, J., Hakonarson, H., Pennell, C. E., & Smith, G. (2013). Common variation contributes to the genetic architecture of social communication traits. Molecular Autism, 4: 34. doi:10.1186/2040-2392-4-34.

    Abstract

    Background: Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. However, little is known about the underlying genetic architecture of this phenotype. Methods: We performed a genome-wide association study on parent-reported social communication problems using items of the children’s communication checklist (age 10 to 11 years) studying single and/or joint marker effects. Analyses were conducted in a large UK population-based birth cohort (Avon Longitudinal Study of Parents and their Children, ALSPAC, N = 5,584) and followed-up within a sample of children with comparable measures from Western Australia (RAINE, N = 1364). Results: Two of our seven independent top signals (P- discovery <1.0E-05) were replicated (0.009 < P- replication ≤0.02) within RAINE and suggested evidence for association at 6p22.1 (rs9257616, meta-P = 2.5E-07) and 14q22.1 (rs2352908, meta-P = 1.1E-06). The signal at 6p22.1 was identified within the olfactory receptor gene cluster within the broader major histocompatibility complex (MHC) region. The strongest candidate locus within this genomic area was TRIM27. This gene encodes an ubiquitin E3 ligase, which is an interaction partner of methyl-CpG-binding domain (MBD) proteins, such as MBD3 and MBD4, and rare protein-coding mutations within MBD3 and MBD4 have been linked to autism. The signal at 14q22.1 was found within a gene-poor region. Single-variant findings were complemented by estimations of the narrow-sense heritability in ALSPAC suggesting that approximately a fifth of the phenotypic variance in social communication traits is accounted for by joint additive effects of genotyped single nucleotide polymorphisms throughout the genome (h2(SE) = 0.18(0.066), P = 0.0027). Conclusion: Overall, our study provides both joint and single-SNP-based evidence for the contribution of common polymorphisms to variation in social communication phenotypes.
  • Rietveld, C. A., Medland, S. E., Derringer, J., Yang, J., Esko, T., Martin, N. W., Westra, H.-J., Shakhbazov, K., Abdellaoui, A., Agrawal, A., Albrecht, E., Alizadeh, B. Z., Amin, N., Barnard, J., Baumeister, S. E., Benke, K. S., Bielak, L. F., Boatman, J. A., Boyle, P. A., Davies, G. and 184 moreRietveld, C. A., Medland, S. E., Derringer, J., Yang, J., Esko, T., Martin, N. W., Westra, H.-J., Shakhbazov, K., Abdellaoui, A., Agrawal, A., Albrecht, E., Alizadeh, B. Z., Amin, N., Barnard, J., Baumeister, S. E., Benke, K. S., Bielak, L. F., Boatman, J. A., Boyle, P. A., Davies, G., de Leeuw, C., Eklund, N., Evans, D. S., Ferhmann, R., Fischer, K., Gieger, C., Gjessing, H. K., Hägg, S., Harris, J. R., Hayward, C., Holzapfel, C., Ibrahim-Verbaas, C. A., Ingelsson, E., Jacobsson, B., Joshi, P. K., Jugessur, A., Kaakinen, M., Kanoni, S., Karjalainen, J., Kolcic, I., Kristiansson, K., Kutalik, Z., Lahti, J., Lee, S. H., Lin, P., Lind, P. A., Liu, Y., Lohman, K., Loitfelder, M., McMahon, G., Vidal, P. M., Meirelles, O., Milani, L., Myhre, R., Nuotio, M.-L., Oldmeadow, C. J., Petrovic, K. E., Peyrot, W. J., Polasek, O., Quaye, L., Reinmaa, E., Rice, J. P., Rizzi, T. S., Schmidt, H., Schmidt, R., Smith, A. V., Smith, J. A., Tanaka, T., Terracciano, A., van der Loos, M. J. H. M., Vitart, V., Völzke, H., Wellmann, J., Yu, L., Zhao, W., Allik, J., Attia, J. R., Bandinelli, S., Bastardot, F., Beauchamp, J., Bennett, D. A., Berger, K., Bierut, L. J., Boomsma, D. I., Bültmann, U., Campbell, H., Chabris, C. F., Cherkas, L., Chung, M. K., Cucca, F., de Andrade, M., De Jager, P. L., De Neve, J.-E., Deary, I. J., Dedoussis, G. V., Deloukas, P., Dimitriou, M., Eiríksdóttir, G., Elderson, M. F., Eriksson, J. G., Evans, D. M., Faul, J. D., Ferrucci, L., Garcia, M. E., Grönberg, H., Guðnason, V., Hall, P., Harris, J. M., Harris, T. B., Hastie, N. D., Heath, A. C., Hernandez, D. G., Hoffmann, W., Hofman, A., Holle, R., Holliday, E. G., Hottenga, J.-J., Iacono, W. G., Illig, T., Järvelin, M.-R., Kähönen, M., Kaprio, J., Kirkpatrick, R. M., Kowgier, M., Latvala, A., Launer, L. J., Lawlor, D. A., Lehtimäki, T., Li, J., Lichtenstein, P., Lichtner, P., Liewald, D. C., Madden, P. A., Magnusson, P. K. E., Mäkinen, T. E., Masala, M., McGue, M., Metspalu, A., Mielck, A., Miller, M. B., Montgomery, G. W., Mukherjee, S., Nyholt, D. R., Oostra, B. A., Palmer, L. J., Palotie, A., Penninx, B. W. J. H., Perola, M., Peyser, P. A., Preisig, M., Räikkönen, K., Raitakari, O. T., Realo, A., Ring, S. M., Ripatti, S., Rivadeneira, F., Rudan, I., Rustichini, A., Salomaa, V., Sarin, A.-P., Schlessinger, D., Scott, R. J., Snieder, H., St Pourcain, B., Starr, J. M., Sul, J. H., Surakka, I., Svento, R., Teumer, A., Tiemeier, H., van Rooij, F. J. A., Van Wagoner, D. R., Vartiainen, E., Viikari, J., Vollenweider, P., Vonk, J. M., Waeber, G., Weir, D. R., Wichmann, H.-E., Widen, E., Willemsen, G., Wilson, J. F., Wright, A. F., Conley, D., Davey-Smith, G., Franke, L., Groenen, P. J. F., Hofman, A., Johannesson, M., Kardia, S. L. R., Krueger, R. F., Laibson, D., Martin, N. G., Meyer, M. N., Posthuma, D., Thurik, A. R., Timpson, N. J., Uitterlinden, A. G., van Duijn, C. M., Visscher, P. M., Benjamin, D. J., Cesarini, D., Koellinger, P. D., & Study LifeLines Cohort (2013). GWAS of 126,559 individuals identifies genetic variants associated with educational attainment. Science, 340(6139), 1467-1471. doi:10.1126/science.1235488.

    Abstract

    A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.

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  • Van der Valk, R. J. P., Duijts, L., Timpson, N. J., Salam, M. T., Standl, M., Curtin, J. A., Genuneit, J., Kerhof, M., Kreiner-Møller, E., Cáceres, A., Gref, A., Liang, L. L., Taal, H. R., Bouzigon, E., Demenais, F., Nadif, R., Ober, C., Thompson, E. E., Estrada, K., Hofman, A. and 39 moreVan der Valk, R. J. P., Duijts, L., Timpson, N. J., Salam, M. T., Standl, M., Curtin, J. A., Genuneit, J., Kerhof, M., Kreiner-Møller, E., Cáceres, A., Gref, A., Liang, L. L., Taal, H. R., Bouzigon, E., Demenais, F., Nadif, R., Ober, C., Thompson, E. E., Estrada, K., Hofman, A., Uitterlinden, A. G., van Duijn, C., Rivadeneira, F., Li, X., Eckel, S. P., Berhane, K., Gauderman, W. J., Granell, R., Evans, D. M., St Pourcain, B., McArdle, W., Kemp, J. P., Smith, G. D., Tiesler, C. M. T., Flexeder, C., Simpson, A., Murray, C. S., Fuchs, O., Postma, D. S., Bønnelykke, K., Torrent, M., Andersson, M., Sleiman, P., Hakonarson, H., Cookson, W. O., Moffatt, M. F., Paternoster, L., Melén, E., Sunyer, J., Bisgaard, H., Koppelman, G. H., Ege, M., Custovic, A., Heinrich, J., Gilliland, F. D., Henderson, A. J., Jaddoe, V. W. V., de Jongste, J. C., & EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium (2013). Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants. Journal of Allergy and Clinical Immunology, 134(1), 46-55. doi:10.1016/j.jaci.2013.08.053.

    Abstract

    BACKGROUND: The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes. OBJECTIVE: We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma. METHODS: Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110). RESULTS: We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 × 10(-10)) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 × 10(-9)), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 × 10(-8)) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. CONCLUSION: This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma.
  • Verhoeven, V. J. M., Hysi, P. G., Wojciechowski, R., Fan, Q., Guggenheim, J. A., Höhn, R., MacGregor, S., Hewitt, A. W., Nag, A., Cheng, C.-Y., Yonova-Doing, E., Zhou, X., Ikram, M. K., Buitendijk, G. H. S., McMahon, G., Kemp, J. P., St Pourcain, B., Simpson, C. L., Mäkelä, K.-M., Lehtimäki, T. and 90 moreVerhoeven, V. J. M., Hysi, P. G., Wojciechowski, R., Fan, Q., Guggenheim, J. A., Höhn, R., MacGregor, S., Hewitt, A. W., Nag, A., Cheng, C.-Y., Yonova-Doing, E., Zhou, X., Ikram, M. K., Buitendijk, G. H. S., McMahon, G., Kemp, J. P., St Pourcain, B., Simpson, C. L., Mäkelä, K.-M., Lehtimäki, T., Kähönen, M., Paterson, A. D., Hosseini, S. M., Wong, H. S., Xu, L., Jonas, J. B., Pärssinen, O., Wedenoja, J., Yip, S. P., Ho, D. W. H., Pang, C. P., Chen, L. J., Burdon, K. P., Craig, J. E., Klein, B. E. K., Klein, R., Haller, T., Metspalu, A., Khor, C.-C., Tai, E.-S., Aung, T., Vithana, E., Tay, W.-T., Barathi, V. A., Chen, P., Li, R., Liao, J., Zheng, Y., Ong, R. T., Döring, A., Evans, D. M., Timpson, N. J., Verkerk, A. J. M. H., Meitinger, T., Raitakari, O., Hawthorne, F., Spector, T. D., Karssen, L. C., Pirastu, M., Murgia, F., Ang, W., Mishra, A., Montgomery, G. W., Pennell, C. E., Cumberland, P. M., Cotlarciuc, I., Mitchell, P., Wang, J. J., Schache, M., Janmahasatian, S., Janmahasathian, S., Igo, R. P., Lass, J. H., Chew, E., Iyengar, S. K., Gorgels, T. G. M. F., Rudan, I., Hayward, C., Wright, A. F., Polasek, O., Vatavuk, Z., Wilson, J. F., Fleck, B., Zeller, T., Mirshahi, A., Müller, C., Uitterlinden, A. G., Rivadeneira, F., Vingerling, J. R., Hofman, A., Oostra, B. A., Amin, N., Bergen, A. A. B., Teo, Y.-Y., Rahi, J. S., Vitart, V., Williams, C., Baird, P. N., Wong, T.-Y., Oexle, K., Pfeiffer, N., Mackey, D. A., Young, T. L., van Duijn, C. M., Saw, S.-M., Bailey-Wilson, J. E., Stambolian, D., Klaver, C. C., Hammond, C. J., Consortium for Refractive Error and Myopia (CREAM), The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group, Wellcome Trust Case Control Consortium 2 (WTCCC2), & The Fuchs' Genetics Multi-Center Study Group (2013). Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia. Nature Genetics, 45(3), 314-318. doi:10.1038/ng.2554.

    Abstract

    Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.
  • Guggenheim, J. A., Northstone, K., McMahon, G., Ness, A. R., Deere, K., Mattocks, C., St Pourcain, B., & Williams, C. (2012). Time outdoors and physical activity as predictors of incident myopia in childhood: a prospective cohort study. Investigative Ophthalmology and Visual Science, 53(6), 2856-2865. doi:10.1167/iovs.11-9091.

    Abstract

    PURPOSE: Time spent in "sports/outdoor activity" has shown a negative association with incident myopia during childhood. We investigated the association of incident myopia with time spent outdoors and physical activity separately. METHODS: Participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) were assessed by noncycloplegic autorefraction at ages 7, 10, 11, 12, and 15 years, and classified as myopic (≤-1 diopters) or as emmetropic/hyperopic (≥-0.25 diopters) at each visit (N = 4,837-7,747). Physical activity at age 11 years was measured objectively using an accelerometer, worn for 1 week. Time spent outdoors was assessed via a parental questionnaire administered when children were aged 8-9 years. Variables associated with incident myopia were examined using Cox regression. RESULTS: In analyses using all available data, both time spent outdoors and physical activity were associated with incident myopia, with time outdoors having the larger effect. The results were similar for analyses restricted to children classified as either nonmyopic or emmetropic/hyperopic at age 11 years. Thus, for children nonmyopic at age 11, the hazard ratio (95% confidence interval, CI) for incident myopia was 0.66 (0.47-0.93) for a high versus low amount of time spent outdoors, and 0.87 (0.76-0.99) per unit standard deviation above average increase in moderate/vigorous physical activity. CONCLUSION: Time spent outdoors was predictive of incident myopia independently of physical activity level. The greater association observed for time outdoors suggests that the previously reported link between "sports/outdoor activity" and incident myopia is due mainly to its capture of information relating to time outdoors rather than physical activity.
  • Ikram, M. A., Fornage, M., Smith, A. V., Seshadri, S., Schmidt, R., Debette, S., Vrooman, H. A., Sigurdsson, S., Ropele, S., Taal, H. R., Mook-Kanamori, D. O., Coker, L. H., Longstreth, W. T., Niessen, W. J., DeStefano, A. L., Beiser, A., Zijdenbos, A. P., Struchalin, M., Jack, C. R., Rivadeneira, F. and 37 moreIkram, M. A., Fornage, M., Smith, A. V., Seshadri, S., Schmidt, R., Debette, S., Vrooman, H. A., Sigurdsson, S., Ropele, S., Taal, H. R., Mook-Kanamori, D. O., Coker, L. H., Longstreth, W. T., Niessen, W. J., DeStefano, A. L., Beiser, A., Zijdenbos, A. P., Struchalin, M., Jack, C. R., Rivadeneira, F., Uitterlinden, A. G., Knopman, D. S., Hartikainen, A.-L., Pennell, C. E., Thiering, E., Steegers, E. A. P., Hakonarson, H., Heinrich, J., Palmer, L. J., Jarvelin, M.-R., McCarthy, M. I., Grant, S. F. A., St Pourcain, B., Timpson, N. J., Smith, G. D., Sovio, U., Nalls, M. A., Au, R., Hofman, A., Gudnason, H., van der Lugt, A., Harris, T. B., Meeks, W. M., Vernooij, M. W., van Buchem, M. A., Catellier, D., Jaddoe, V. W. V., Gudnason, V., Windham, B. G., Wolf, P. A., van Duijn, C. M., Mosley, T. H., Schmidt, H., Launer, L. J., Breteler, M. M. B., DeCarli, C., Consortiumthe Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, & Early Growth Genetics (EGG) Consortium (2012). Common variants at 6q22 and 17q21 are associated with intracranial volume. Nature Genetics, 44(5), 539-544. doi:10.1038/ng.2245.

    Abstract

    During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10(-3) for 6q22 and 1.2 × 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
  • Paternoster, L., Zhurov, A., Toma, A., Kemp, J., St Pourcain, B., Timpson, N., McMahon, G., McArdle, W., Ring, S., Smith, G., Richmond, S., & Evans, D. (2012). Genome-wide Association Study of Three-Dimensional Facial Morphology Identifies a Variant in PAX3 Associated with Nasion Position. The American Journal of Human Genetics, 90(3), 478-485. doi:10.1016/j.ajhg.2011.12.021.

    Abstract

    Craniofacial morphology is highly heritable, but little is known about which genetic variants influence normal facial variation in the general population. We aimed to identify genetic variants associated with normal facial variation in a population-based cohort of 15-year-olds from the Avon Longitudinal Study of Parents and Children. 3D high-resolution images were obtained with two laser scanners, these were merged and aligned, and 22 landmarks were identified and their x, y, and z coordinates used to generate 54 3D distances reflecting facial features. 14 principal components (PCs) were also generated from the landmark locations. We carried out genome-wide association analyses of these distances and PCs in 2,185 adolescents and attempted to replicate any significant associations in a further 1,622 participants. In the discovery analysis no associations were observed with the PCs, but we identified four associations with the distances, and one of these, the association between rs7559271 in PAX3 and the nasion to midendocanthion distance (n-men), was replicated (p = 4 × 10−7). In a combined analysis, each G allele of rs7559271 was associated with an increase in n-men distance of 0.39 mm (p = 4 × 10−16), explaining 1.3% of the variance. Independent associations were observed in both the z (nasion prominence) and y (nasion height) dimensions (p = 9 × 10−9 and p = 9 × 10−10, respectively), suggesting that the locus primarily influences growth in the yz plane. Rare variants in PAX3 are known to cause Waardenburg syndrome, which involves deafness, pigmentary abnormalities, and facial characteristics including a broad nasal bridge. Our findings show that common variants within this gene also influence normal craniofacial development.
  • Relton, C. L., Groom, A., St Pourcain, B., Sayers, A. E., Swan, D. C., Embleton, N. D., Pearce, M. S., Ring, S. M., Northstone, K., Tobias, J. H., Trakalo, J., Ness, A. R., Shaheen, S. O., & Davey Smith, G. (2012). DNA Methylation Patterns in Cord Blood DNA and Body Size in Childhood. PLoS ONE, 7(3): e31821. doi:10.1371/journal.pone.0031821.

    Abstract

    BACKGROUND: Epigenetic markings acquired in early life may have phenotypic consequences later in development through their role in transcriptional regulation with relevance to the developmental origins of diseases including obesity. The goal of this study was to investigate whether DNA methylation levels at birth are associated with body size later in childhood. PRINCIPAL FINDINGS: A study design involving two birth cohorts was used to conduct transcription profiling followed by DNA methylation analysis in peripheral blood. Gene expression analysis was undertaken in 24 individuals whose biological samples and clinical data were collected at a mean ± standard deviation (SD) age of 12.35 (0.95) years, the upper and lower tertiles of body mass index (BMI) were compared with a mean (SD) BMI difference of 9.86 (2.37) kg/m(2). This generated a panel of differentially expressed genes for DNA methylation analysis which was then undertaken in cord blood DNA in 178 individuals with body composition data prospectively collected at a mean (SD) age of 9.83 (0.23) years. Twenty-nine differentially expressed genes (>}1.2-fold and p{<10(-4)) were analysed to determine DNA methylation levels at 1-3 sites per gene. Five genes were unmethylated and DNA methylation in the remaining 24 genes was analysed using linear regression with bootstrapping. Methylation in 9 of the 24 (37.5%) genes studied was associated with at least one index of body composition (BMI, fat mass, lean mass, height) at age 9 years, although only one of these associations remained after correction for multiple testing (ALPL with height, p(Corrected) = 0.017). CONCLUSIONS: DNA methylation patterns in cord blood show some association with altered gene expression, body size and composition in childhood. The observed relationship is correlative and despite suggestion of a mechanistic epigenetic link between in utero life and later phenotype, further investigation is required to establish causality.
  • Scott, R. A., Lagou, V., Welch, R. P., Wheeler, E., Montasser, M. E., Luan, J., Mägi, R., Strawbridge, R. J., Rehnberg, E., Gustafsson, S., Kanoni, S., Rasmussen-Torvik, L. J., Yengo, L., Lecoeur, C., Shungin, D., Sanna, S., Sidore, C., Johnson, P. C. D., Jukema, J. W., Johnson, T. and 195 moreScott, R. A., Lagou, V., Welch, R. P., Wheeler, E., Montasser, M. E., Luan, J., Mägi, R., Strawbridge, R. J., Rehnberg, E., Gustafsson, S., Kanoni, S., Rasmussen-Torvik, L. J., Yengo, L., Lecoeur, C., Shungin, D., Sanna, S., Sidore, C., Johnson, P. C. D., Jukema, J. W., Johnson, T., Mahajan, A., Verweij, N., Thorleifsson, G., Hottenga, J.-J., Shah, S., Smith, A. V., Sennblad, B., Gieger, C., Salo, P., Perola, M., Timpson, N. J., Evans, D. M., St Pourcain, B., Wu, Y., Andrews, J. S., Hui, J., Bielak, L. F., Zhao, W., Horikoshi, M., Navarro, P., Isaacs, A., O'Connell, J. R., Stirrups, K., Vitart, V., Hayward, C., Esko, T., Mihailov, E., Fraser, R. M., Fall, T., Voight, B. F., Raychaudhuri, S., Chen, H., Lindgren, C. M., Morris, A. P., Rayner, N. W., Robertson, N., Rybin, D., Liu, C.-T., Beckmann, J. S., Willems, S. M., Chines, P. S., Jackson, A. U., Kang, H. M., Stringham, H. M., Song, K., Tanaka, T., Peden, J. F., Goel, A., Hicks, A. A., An, P., Müller-Nurasyid, M., Franco-Cereceda, A., Folkersen, L., Marullo, L., Jansen, H., Oldehinkel, A. J., Bruinenberg, M., Pankow, J. S., North, K. E., Forouhi, N. G., Loos, R. J. F., Edkins, S., Varga, T. V., Hallmans, G., Oksa, H., Antonella, M., Nagaraja, R., Trompet, S., Ford, I., Bakker, S. J. L., Kong, A., Kumari, M., Gigante, B., Herder, C., Munroe, P. B., Caulfield, M., Antti, J., Mangino, M., Small, K., Miljkovic, I., Liu, Y., Atalay, M., Kiess, W., James, A. L., Rivadeneira, F., Uitterlinden, A. G., Palmer, C. N. A., Doney, A. S. F., Willemsen, G., Smit, J. H., Campbell, S., Polasek, O., Bonnycastle, L. L., Hercberg, S., Dimitriou, M., Bolton, J. L., Fowkes, G. R., Kovacs, P., Lindström, J., Zemunik, T., Bandinelli, S., Wild, S. H., Basart, H. V., Rathmann, W., Grallert, H., Maerz, W., Kleber, M. E., Boehm, B. O., Peters, A., Pramstaller, P. P., Province, M. A., Borecki, I. B., Hastie, N. D., Rudan, I., Campbell, H., Watkins, H., Farrall, M., Stumvoll, M., Ferrucci, L., Waterworth, D. M., Bergman, R. N., Collins, F. S., Tuomilehto, J., Watanabe, R. M., de Geus, E. J. C., Penninx, B. W., Hofman, A., Oostra, B. A., Psaty, B. M., Vollenweider, P., Wilson, J. F., Wright, A. F., Hovingh, G. K., Metspalu, A., Uusitupa, M., Magnusson, P. K. E., Kyvik, K. O., Kaprio, J., Price, J. F., Dedoussis, G. V., Deloukas, P., Meneton, P., Lind, L., Boehnke, M., Shuldiner, A. R., van Duijn, C. M., Morris, A. D., Toenjes, A., Peyser, P. A., Beilby, J. P., Körner, A., Kuusisto, J., Laakso, M., Bornstein, S. R., Schwarz, P. E. H., Lakka, T. A., Rauramaa, R., Adair, L. S., Smith, G. D., Spector, T. D., Illig, T., de Faire, U., Hamsten, A., Gudnason, V., Kivimaki, M., Hingorani, A., Keinanen-Kiukaanniemi, S. M., Saaristo, T. E., Boomsma, D. I., Stefansson, K., van der Harst, P., Dupuis, J., Pedersen, N. L., Sattar, N., Harris, T. B., Cucca, F., Ripatti, S., Salomaa, V., Mohlke, K. L., Balkau, B., Froguel, P., Pouta, A., Jarvelin, M.-R., Wareham, N. J., Bouatia-Naji, N., McCarthy, M. I., Franks, P. W., Meigs, J. B., Teslovich, T. M., Florez, J. C., Langenberg, C., Ingelsson, E., Prokopenko, I., Barroso, I., & Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium (2012). Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nature Genetics, 44(9), 991-1005. doi:10.1038/ng.2385.

    Abstract

    Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
  • Taal, H. R., St Pourcain, B., Thiering, E., Das, S., Mook-Kanamori, D. O., Warrington, N. M., Kaakinen, M., Kreiner-Møller, E., Bradfield, J. P., Freathy, R. M., Geller, F., Guxens, M., Cousminer, D. L., Kerkhof, M., Timpson, N. J., Ikram, M. A., Beilin, L. J., Bønnelykke, K., Buxton, J. L., Charoen, P. and 68 moreTaal, H. R., St Pourcain, B., Thiering, E., Das, S., Mook-Kanamori, D. O., Warrington, N. M., Kaakinen, M., Kreiner-Møller, E., Bradfield, J. P., Freathy, R. M., Geller, F., Guxens, M., Cousminer, D. L., Kerkhof, M., Timpson, N. J., Ikram, M. A., Beilin, L. J., Bønnelykke, K., Buxton, J. L., Charoen, P., Chawes, B. L. K., Eriksson, J., Evans, D. M., Hofman, A., Kemp, J. P., Kim, C. E., Klopp, N., Lahti, J., Lye, S. J., McMahon, G., Mentch, F. D., Müller-Nurasyid, M., O'Reilly, P. F., Prokopenko, I., Rivadeneira, F., Steegers, E. A. P., Sunyer, J., Tiesler, C., Yaghootkar, H., Breteler, M. M. B., Decarli, C., Breteler, M. M. B., Debette, S., Fornage, M., Gudnason, V., Launer, L. J., van der Lugt, A., Mosley, T. H., Seshadri, S., Smith, A. V., Vernooij, M. W., Blakemore, A. I. F., Chiavacci, R. M., Feenstra, B., Fernandez-Banet, J., Grant, S. F. A., Hartikainen, A.-L., van der Heijden, A. J., Iñiguez, C., Lathrop, M., McArdle, W. L., Mølgaard, A., Newnham, J. P., Palmer, L. J., Palotie, A., Pouta, A., Ring, S. M., Sovio, U., Standl, M., Uitterlinden, A. G., Wichmann, H.-E., Vissing, N. H., DeCarli, C., van Duijn, C. M., McCarthy, M. I., Koppelman, G. H., Estivill, X., Hattersley, A. T., Melbye, M., Bisgaard, H., Pennell, C. E., Widen, E., Hakonarson, H., Smith, G. D., Heinrich, J., Jarvelin, M.-R., Jaddoe, V. W. V., The Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium, EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium, & Early Growth Genetics (EGG) Consortium (2012). Common variants at 12q15 and 12q24 are associated with infant head circumference. Nature Genetics, 44(5), 532-538. doi:10.1038/ng.2238.

    Abstract

    To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
  • Glaser, B., Gunnell, D., Timpson, N. J., Joinson, C., Zammit, S., Smith, G. D., & Lewis, G. (2011). Age- and puberty-dependent association between IQ score in early childhood and depressive symptoms in adolescence. Psychological Medicine, 41(2), 333-343. doi:10.1017/S0033291710000814.

    Abstract

    BACKGROUND: Lower cognitive functioning in early childhood has been proposed as a risk factor for depression in later life but its association with depressive symptoms during adolescence has rarely been investigated. Our study examines the relationship between total intelligence quotient (IQ) score at age 8 years, and depressive symptoms at 11, 13, 14 and 17 years. METHOD: Study participants were 5250 children and adolescents from the Avon Longitudinal Study of Parents and their Children (ALSPAC), UK, for whom longitudinal data on depressive symptoms were available. IQ was assessed with the Wechsler Intelligence Scale for Children III, and self-reported depressive symptoms were measured with the Short Mood and Feelings Questionnaire (SMFQ). RESULTS: Multi-level analysis on continuous SMFQ scores showed that IQ at age 8 years was inversely associated with depressive symptoms at age 11 years, but the association changed direction by age 13 and 14 years (age-IQ interaction, p<}0.0001; age squared-IQ interaction, p{<}0.0001) when a higher IQ score was associated with a higher risk of depressive symptoms. This change in IQ effect was also found in relation to pubertal stage (pubertal stage-IQ interaction, 0.00049{

    Additional information

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  • Munafò, M. R., Freathy, R. M., Ring, S. M., St Pourcain, B., & Smith, G. D. (2011). Association of COMT Val108/158Met Genotype and Cigarette Smoking in Pregnant Women. Nicotine & Tobacco Research, 13(2), 55-63. doi:10.1093/ntr/ntq209.

    Abstract

    INTRODUCTION: Smoking behaviors, including heaviness of smoking and smoking cessation, are known to be under a degree of genetic influence. The enzyme catechol O-methyltransferase (COMT) is of relevance in studies of smoking behavior and smoking cessation due to its presence in dopaminergic brain regions. While the COMT gene is therefore one of the more promising candidate genes for smoking behavior, some inconsistencies have begun to emerge. METHODS: We explored whether the rs4680 A (Met) allele of the COMT gene predicts increased heaviness of smoking and reduced likelihood of smoking cessation in a large population-based cohort of pregnant women. We further conducted a meta-analysis of published data from community samples investigating the association of this polymorphism with heaviness of smoking and smoking status. RESULTS: In our primary sample, the A (Met) allele was associated with increased heaviness of smoking before pregnancy but not with the odds of continuing to smoke in pregnancy either in the first trimester or in the third trimester. Meta-analysis also indicated modest evidence of association of the A (Met) allele with increased heaviness of smoking but not with persistent smoking. CONCLUSIONS: Our data suggest a weak association between COMT genotype and heaviness of smoking, which is supported by our meta-analysis. However, it should be noted that the strength of evidence for this association was modest. Neither our primary data nor our meta-analysis support an association between COMT genotype and smoking cessation. Therefore, COMT remains a plausible candidate gene for smoking behavior phenotypes, in particular, heaviness of smoking.
  • Paternoster, L., Evans, D. M., Aagaard Nohr, E., Holst, C., Gaborieau, V., Brennan, P., Prior Gjesing, A., Grarup, N., Witte, D. R., Jørgensen, T., Linneberg, A., Lauritzen, T., Sandbaek, A., Hansen, T., Pedersen, O., Elliott, K. S., Kemp, J. P., St Pourcain, B., McMahon, G., Zelenika, D. and 5 morePaternoster, L., Evans, D. M., Aagaard Nohr, E., Holst, C., Gaborieau, V., Brennan, P., Prior Gjesing, A., Grarup, N., Witte, D. R., Jørgensen, T., Linneberg, A., Lauritzen, T., Sandbaek, A., Hansen, T., Pedersen, O., Elliott, K. S., Kemp, J. P., St Pourcain, B., McMahon, G., Zelenika, D., Hager, J., Lathrop, M., Timpson, N. J., Davey Smith, G., & Sørensen, T. I. A. (2011). Genome-Wide Population-Based Association Study of Extremely Overweight Young Adults – The GOYA Study. PLoS ONE, 6(9): e24303. doi:10.1371/journal.pone.0024303.

    Abstract

    Background Thirty-two common variants associated with body mass index (BMI) have been identified in genome-wide association studies, explaining ∼1.45% of BMI variation in general population cohorts. We performed a genome-wide association study in a sample of young adults enriched for extremely overweight individuals. We aimed to identify new loci associated with BMI and to ascertain whether using an extreme sampling design would identify the variants known to be associated with BMI in general populations. Methodology/Principal Findings From two large Danish cohorts we selected all extremely overweight young men and women (n = 2,633), and equal numbers of population-based controls (n = 2,740, drawn randomly from the same populations as the extremes, representing ∼212,000 individuals). We followed up novel (at the time of the study) association signals (p<}0.001) from the discovery cohort in a genome-wide study of 5,846 Europeans, before attempting to replicate the most strongly associated 28 SNPs in an independent sample of Danish individuals (n = 20,917) and a population-based cohort of 15-year-old British adolescents (n = 2,418). Our discovery analysis identified SNPs at three loci known to be associated with BMI with genome-wide confidence (P{<}5×10−8; FTO, MC4R and FAIM2). We also found strong evidence of association at the known TMEM18, GNPDA2, SEC16B, TFAP2B, SH2B1 and KCTD15 loci (p{<}0.001), and nominal association (p{<0.05) at a further 8 loci known to be associated with BMI. However, meta-analyses of our discovery and replication cohorts identified no novel associations. Significance Our results indicate that the detectable genetic variation associated with extreme overweight is very similar to that previously found for general BMI. This suggests that population-based study designs with enriched sampling of individuals with the extreme phenotype may be an efficient method for identifying common variants that influence quantitative traits and a valid alternative to genotyping all individuals in large population-based studies, which may require tens of thousands of subjects to achieve similar power.
  • St Pourcain, B., Mandy, W. P., Heron, J., Golding, J., Davey Smith, G., & Skuse, D. H. (2011). Links between co-occurring social-communication and hyperactive-inattentive trait trajectories. Journal of the American Academy of Child & Adolescent Psychiatry, 50(9), 892-902.e5. doi:10.1016/j.jaac.2011.05.015.

    Abstract

    OBJECTIVE: There is overlap between an autistic and hyperactive-inattentive symptomatology when studied cross-sectionally. This study is the first to examine the longitudinal pattern of association between social-communication deficits and hyperactive-inattentive symptoms in the general population, from childhood through adolescence. We explored the interrelationship between trajectories of co-occurring symptoms, and sought evidence for shared prenatal/perinatal risk factors. METHOD: Study participants were 5,383 singletons of white ethnicity from the Avon Longitudinal Study of Parents and Children (ALSPAC). Multiple measurements of hyperactive-inattentive traits (Strengths and Difficulties Questionnaire) and autistic social-communication impairment (Social Communication Disorder Checklist) were obtained between 4 and 17 years. Both traits and their trajectories were modeled in parallel using latent class growth analysis (LCGA). Trajectory membership was subsequently investigated with respect to prenatal/perinatal risk factors. RESULTS: LCGA analysis revealed two distinct social-communication trajectories (persistently impaired versus low-risk) and four hyperactive-inattentive trait trajectories (persistently impaired, intermediate, childhood-limited and low-risk). Autistic symptoms were more stable than those of attention-deficit/hyperactivity disorder (ADHD) behaviors, which showed greater variability. Trajectories for both traits were strongly but not reciprocally interlinked, such that the majority of children with a persistent hyperactive-inattentive symptomatology also showed persistent social-communication deficits but not vice versa. Shared predictors, especially for trajectories of persistent impairment, were maternal smoking during the first trimester, which included familial effects, and a teenage pregnancy. CONCLUSIONS: Our longitudinal study reveals that a complex relationship exists between social-communication and hyperactive-inattentive traits. Patterns of association change over time, with corresponding implications for removing exclusivity criteria for ASD and ADHD, as proposed for DSM-5.
  • Freathy, R. M., Mook-Kanamori, D. O., Sovio, U., Prokopenko, I., Timpson, N. J., Berry, D. J., Warrington, N. M., Widen, E., Hottenga, J. J., Kaakinen, M., Lange, L. A., Bradfield, J. P., Kerkhof, M., Marsh, J. A., Mägi, R., Chen, C.-M., Lyon, H. N., Kirin, M., Adair, L. S., Aulchenko, Y. S. and 64 moreFreathy, R. M., Mook-Kanamori, D. O., Sovio, U., Prokopenko, I., Timpson, N. J., Berry, D. J., Warrington, N. M., Widen, E., Hottenga, J. J., Kaakinen, M., Lange, L. A., Bradfield, J. P., Kerkhof, M., Marsh, J. A., Mägi, R., Chen, C.-M., Lyon, H. N., Kirin, M., Adair, L. S., Aulchenko, Y. S., Bennett, A. J., Borja, J. B., Bouatia-Naji, N., Charoen, P., Coin, L. J. M., Cousminer, D. L., de Geus, E. J. C., Deloukas, P., Elliott, P., Evans, D. M., Froguel, P., Glaser, B., Groves, C. J., Hartikainen, A.-L., Hassanali, N., Hirschhorn, J. N., Hofman, A., Holly, J. M. P., Hyppönen, E., Kanoni, S., Knight, B. A., Laitinen, J., Lindgren, C. M., McArdle, W. L., O'Reilly, P. F., Pennell, C. E., Postma, D. S., Pouta, A., Ramasamy, A., Rayner, N. W., Ring, S. M., Rivadeneira, F., Shields, B. M., Strachan, D. P., Surakka, I., Taanila, A., Tiesler, C., Uitterlinden, A. G., van Duijn, C. M., Wijga, A. H., Willemsen, G., Zhang, H., Zhao, J., Wilson, J. F., Steegers, E. A. P., Hattersley, A. T., Eriksson, J. G., Peltonen, L., Mohlke, K. L., Grant, S. F. A., Hakonarson, H., Koppelman, G. H., Dedoussis, G. V., Heinrich, J., Gillman, M. W., Palmer, L. J., Frayling, T. M., Boomsma, D. I., Davey Smith, G., Power, C., Jaddoe, V. W. V., Jarvelin, M.-R., McCarthy, M. I., The Genetic Investigation of ANthropometric Traits (GIANT) Consortium, The Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), The Wellcome Trust Case Control Consortium (WTCCC), & the Early Growth Genetics (EGG) Consortium (2010). Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight. Nature Genetics, 42(5), 430-435. doi:10.1038/ng.567.

    Abstract

    To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 10(-15)) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113 g (95% CI 89-137 g) lighter at birth than the 24% with zero or one alleles (P(trend) = 7 x 10(-30)). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.
  • Glaser, B., Ades, A. E., Lewis, S., Emmet, P., Lewis, G., Smith, G. D., & Zammit, S. (2010). Perinatal folate-related exposures and risk of psychotic symptoms in the ALSPAC birth cohort. Schizophrenia Research, 120, 177-183. doi:10.1016/j.schres.2010.03.006.

    Abstract

    BACKGROUND: It is unclear to what extent non-clinical psychotic experiences during childhood and adolescence share underlying aetiological mechanisms with schizophrenia. One candidate mechanism for schizophrenia involves the epigenetic status of the developing fetus, which depends on the internal folate-status of mother and child. Our study examines the relationships between multiple determinants of perinatal folate-status and development of psychotic experiences in adolescence. METHODS: Study participants were up to 5344 mother-child pairs from the Avon Longitudinal Study of Parents and their Children, UK, with information on maternal and/or child MTHFR C677T genotype, maternal folate intake (supplementation at 18/32- weeks gestation; dietary intake at 32- weeks gestation) and psychosis-like symptoms (PLIKS) for children assessed at age 12. RESULTS: Nominal evidence was observed that maternal folate supplementation at 18 weeks increased the odds of PLIKS in children (odds ratio(OR)=1.34; 95%-CI:[1.00;1.76]) and, consistent with this, that children of MTHFR C667T TT homozygous mothers had decreased odds of PLIKS (OR=0.72; 95%CI:[0.50;1.02]; recessive model) with strongest effects in boys (OR=0.44, 95%-CI:[0.22;0.79]; sex-specific p=0.029). None of the reported effects remained significant when corrected for multiple testing. CONCLUSIONS: Overall, this study found no support that maternal/child MTHFR C677T genotype and maternal folate intake during pregnancy contribute to common aetiological pathways that are shared between schizophrenia and non-clinical psychotic symptoms in adolescents, assuming that decreased folate-status increases schizophrenia risk.
  • Glaser, B., Shelton, K. H., & van den Bree, M. B. M. (2010). The moderating role of close friends in the relationship between conduct problems and adolescent substance use. Journal of Adolescent Health, 47(1), 35-42. doi:10.1016/j.jadohealth.2009.12.022.

    Abstract

    PURPOSE: Conduct problems and peer effects are among the strongest risk factors for adolescent substance use and problem use. However, it is unclear to what extent the effects of conduct problems and peer behavior interact, and whether adolescents' capacity to refuse the offer of substances may moderate such links. This study was conducted to examine relationships between conduct problems, close friends' substance use, and refusal assertiveness with adolescents' alcohol use problems, tobacco, and marijuana use. METHODS: We studied a population-based sample of 1,237 individuals from the Cardiff Study of All Wales and North West of England Twins aged 11-18 years. Adolescent and mother-reported information was obtained. Statistical analyses included cross-sectional and prospective logistic regression models and family-based permutations. RESULTS: Conduct problems and close friends' substance use were associated with increased adolescents' substance use, whereas refusal assertiveness was associated with lower use of cigarettes, alcohol, and marijuana. Peer substance use moderated the relationship between conduct problems and alcohol use problems, such that conduct problems were only related to increased risk for alcohol use problems in the presence of substance-using friends. This effect was found in both cross-sectional and prospective analyses and confirmed using the permutation approach. CONCLUSIONS: Reduced opportunities for interaction with alcohol-using peers may lower the risk of alcohol use problems in adolescents with conduct problems.
  • Heid, I. M., Henneman, P., Hicks, A., Coassin, S., Winkler, T., Aulchenko, Y. S., Fuchsberger, C., Song, K., Hivert, M.-F., Waterworth, D. M., Timpson, N. J., Richards, J. B., Perry, J. R. B., Tanaka, T., Amin, N., Kollerits, B., Pichler, I., Oostra, B. A., Thorand, B., Frants, R. R. and 22 moreHeid, I. M., Henneman, P., Hicks, A., Coassin, S., Winkler, T., Aulchenko, Y. S., Fuchsberger, C., Song, K., Hivert, M.-F., Waterworth, D. M., Timpson, N. J., Richards, J. B., Perry, J. R. B., Tanaka, T., Amin, N., Kollerits, B., Pichler, I., Oostra, B. A., Thorand, B., Frants, R. R., Illig, T., Dupuis, J., Glaser, B., Spector, T., Guralnik, J., Egan, J. M., Florez, J. C., Evans, D. M., Soranzo, N., Bandinelli, S., Carlson, O. D., Frayling, T. M., Burling, K., Smith, G. D., Mooser, V., Ferrucci, L., Meigs, J. B., Vollenweider, P., Dijk, K. W. v., Pramstaller, P., Kronenberg, F., & van Duijn, C. M. (2010). Clear detection of ADIPOQ locus as the major gene for plasma adiponectin: Results of genome-wide association analyses including 4659 European individuals. Atherosclerosis, 208(2), 412-420. doi:10.1016/j.atherosclerosis.2009.11.035.

    Abstract

    OBJECTIVE: Plasma adiponectin is strongly associated with various components of metabolic syndrome, type 2 diabetes and cardiovascular outcomes. Concentrations are highly heritable and differ between men and women. We therefore aimed to investigate the genetics of plasma adiponectin in men and women. METHODS: We combined genome-wide association scans of three population-based studies including 4659 persons. For the replication stage in 13795 subjects, we selected the 20 top signals of the combined analysis, as well as the 10 top signals with p-values less than 1.0 x 10(-4) for each the men- and the women-specific analyses. We further selected 73 SNPs that were consistently associated with metabolic syndrome parameters in previous genome-wide association studies to check for their association with plasma adiponectin. RESULTS: The ADIPOQ locus showed genome-wide significant p-values in the combined (p=4.3 x 10(-24)) as well as in both women- and men-specific analyses (p=8.7 x 10(-17) and p=2.5 x 10(-11), respectively). None of the other 39 top signal SNPs showed evidence for association in the replication analysis. None of 73 SNPs from metabolic syndrome loci exhibited association with plasma adiponectin (p>0.01). CONCLUSIONS: We demonstrated the ADIPOQ gene as the only major gene for plasma adiponectin, which explains 6.7% of the phenotypic variance. We further found that neither this gene nor any of the metabolic syndrome loci explained the sex differences observed for plasma adiponectin. Larger studies are needed to identify more moderate genetic determinants of plasma adiponectin.
  • Medland, S. E., Zayats, T., Glaser, B., Nyholt, D. R., Gordon, S. D., Wright, M. J., Montgomery, G. W., Campbell, M. J., Henders, A. K., Timpson, N. J., Peltonen, L., Wolke, D., Ring, S. M., Deloukas, P., Martin, N. G., Smith, G. D., & Evans, D. M. (2010). A variant in LIN28B is associated with 2D:4D finger-length ratio, a putative retrospective biomarker of prenatal testosterone exposure. American Journal of Human Genetics, 86(4), 519-525. doi:10.1016/j.ajhg.2010.02.017.

    Abstract

    The ratio of the lengths of an individual's second to fourth digit (2D:4D) is commonly used as a noninvasive retrospective biomarker for prenatal androgen exposure. In order to identify the genetic determinants of 2D:4D, we applied a genome-wide association approach to 1507 11-year-old children from the Avon Longitudinal Study of Parents and Children (ALSPAC) in whom 2D:4D ratio had been measured, as well as a sample of 1382 12- to 16-year-olds from the Brisbane Adolescent Twin Study. A meta-analysis of the two scans identified a single variant in the LIN28B gene that was strongly associated with 2D:4D (rs314277: p = 4.1 x 10(-8)) and was subsequently independently replicated in an additional 3659 children from the ALSPAC cohort (p = 1.53 x 10(-6)). The minor allele of the rs314277 variant has previously been linked to increased height and delayed age at menarche, but in our study it was associated with increased 2D:4D in the direction opposite to that of previous reports on the correlation between 2D:4D and age at menarche. Our findings call into question the validity of 2D:4D as a simplistic retrospective biomarker for prenatal testosterone exposure.
  • Pillas, D., Hoggart, C. J., Evans, D. M., O'Reilly, P. F., Sipilä, K., Lähdesmäki, R., Millwood, I. Y., Kaakinen, M., Netuveli, G., Blane, D., Charoen, P., Sovio, U., Pouta, A., Freimer, N., Hartikainen, A.-L., Laitinen, J., Vaara, S., Glaser, B., Crawford, P., Timpson, N. J. and 10 morePillas, D., Hoggart, C. J., Evans, D. M., O'Reilly, P. F., Sipilä, K., Lähdesmäki, R., Millwood, I. Y., Kaakinen, M., Netuveli, G., Blane, D., Charoen, P., Sovio, U., Pouta, A., Freimer, N., Hartikainen, A.-L., Laitinen, J., Vaara, S., Glaser, B., Crawford, P., Timpson, N. J., Ring, S. M., Deng, G., Zhang, W., McCarthy, M. I., Deloukas, P., Peltonen, L., Elliott, P., Coin, L. J. M., Smith, G. D., & Jarvelin, M.-R. (2010). Genome-wide association study reveals multiple loci associated with primary tooth development during infancy. PLoS Genetics, 6(2): e1000856. doi:10.1371/journal.pgen.1000856.

    Abstract

    Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<}5x10(-8), and 5 with suggestive association (P{<5x10(-6)). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years.
  • St Pourcain, B., Wang, K., Glessner, J. T., Golding, J., Steer, C., Ring, S. M., Skuse, D. H., Grant, S. F. A., Hakonarson, H., & Davey Smith, G. (2010). Association Between a High-Risk Autism Locus on 5p14 and Social Communication Spectrum Phenotypes in the General Population. American Journal of Psychiatry, 167(11), 1364-1372. doi:10.1176/appi.ajp.2010.09121789.

    Abstract

    Objective: Recent genome-wide analysis identified a genetic variant on 5p14.1 (rs4307059), which is associated with risk for autism spectrum disorder. This study investigated whether rs4307059 also operates as a quantitative trait locus underlying a broader autism phenotype in the general population, focusing specifically on the social communication aspect of the spectrum. Method: Study participants were 7,313 children from the Avon Longitudinal Study of Parents and Children. Single-trait and joint-trait genotype associations were investigated for 29 measures related to language and communication, verbal intelligence, social interaction, and behavioral adjustment, assessed between ages 3 and 12 years. Analyses were performed in one-sided or directed mode and adjusted for multiple testing, trait interrelatedness, and random genotype dropout. Results: Single phenotype analyses showed that an increased load of rs4307059 risk allele is associated with stereotyped conversation and lower pragmatic communication skills, as measured by the Children's Communication Checklist (at a mean age of 9.7 years). In addition a trend toward a higher frequency of identification of special educational needs (at a mean age of 11.8 years) was observed. Variation at rs4307059 was also associated with the phenotypic profile of studied traits. This joint signal was fully explained neither by single-trait associations nor by overall behavioral adjustment problems but suggested a combined effect, which manifested through multiple sub-threshold social, communicative, and cognitive impairments. Conclusions: Our results suggest that common variation at 5p14.1 is associated with social communication spectrum phenotypes in the general population and support the role of rs4307059 as a quantitative trait locus for autism spectrum disorder.
  • Ruano, D., Abecasis, G. R., Glaser, B., Lips, E. S., Cornelisse, L. N., de Jong, A. P. H., Evans, D. M., Davey Smith, G., Timpson, N. J., Smit, A. B., Heutink, P., Verhage, M., & Posthuma, D. (2010). Functional gene group analysis reveals a role of synaptic heterotrimeric G proteins in cognitive ability. American Journal of Human Genetics, 86(2), 113-125. doi:10.1016/j.ajhg.2009.12.006.

    Abstract

    Although cognitive ability is a highly heritable complex trait, only a few genes have been identified, explaining relatively low proportions of the observed trait variation. This implies that hundreds of genes of small effect may be of importance for cognitive ability. We applied an innovative method in which we tested for the effect of groups of genes defined according to cellular function (functional gene group analysis). Using an initial sample of 627 subjects, this functional gene group analysis detected that synaptic heterotrimeric guanine nucleotide binding proteins (G proteins) play an important role in cognitive ability (P(EMP) = 1.9 x 10(-4)). The association with heterotrimeric G proteins was validated in an independent population sample of 1507 subjects. Heterotrimeric G proteins are central relay factors between the activation of plasma membrane receptors by extracellular ligands and the cellular responses that these induce, and they can be considered a point of convergence, or a "signaling bottleneck." Although alterations in synaptic signaling processes may not be the exclusive explanation for the association of heterotrimeric G proteins with cognitive ability, such alterations may prominently affect the properties of neuronal networks in the brain in such a manner that impaired cognitive ability and lower intelligence are observed. The reported association of synaptic heterotrimeric G proteins with cognitive ability clearly points to a new direction in the study of the genetic basis of cognitive ability.
  • Glaser, B., & Holmans, P. (2009). Comparison of methods for combining case-control and family-based association studies. Human Heredity, 68(2), 106-116. doi:10.1159/000212503.

    Abstract

    OBJECTIVES: Combining the analysis of family-based samples with unrelated individuals can enhance the power of genetic association studies. Various combined analysis techniques have been recently developed; as yet, there have been no comparisons of their power, or robustness to confounding factors. We investigated empirically the power of up to six combined methods using simulated samples of trios and unrelated cases/controls (TDTCC), trios and unrelated controls (TDTC), and affected sibpairs with parents and unrelated cases/controls (ASPFCC). METHODS: We simulated multiplicative, dominant and recessive models with varying risk parameters in single samples. Additionally, we studied false-positive rates and investigated, if possible, the coverage of the true genetic effect (TDTCC). RESULTS/CONCLUSIONS: Under the TDTCC design, we identified four approaches with equivalent power and false-positive rates. Combined statistics were more powerful than single-sample statistics or a pooled chi(2)-statistic when risk parameters were similar in single samples. Adding parental information to the CC part of the joint likelihood increased the power of generalised logistic regression under the TDTC but not the TDTCC scenario. Formal testing of differences between risk parameters in subsamples was the most sensitive approach to avoid confounding in combined analysis. Non-parametric analysis based on Monte-Carlo testing showed the highest power for ASPFCC samples.
  • Richards, J. B., Waterworth, D., O'Rahilly, S., Hivert, M.-F., Loos, R. J. F., Perry, J. R. B., Tanaka, T., Timpson, N. J., Semple, R. K., Soranzo, N., Song, K., Rocha, N., Grundberg, E., Dupuis, J., Florez, J. C., Langenberg, C., Prokopenko, I., Saxena, R., Sladek, R., Aulchenko, Y. and 47 moreRichards, J. B., Waterworth, D., O'Rahilly, S., Hivert, M.-F., Loos, R. J. F., Perry, J. R. B., Tanaka, T., Timpson, N. J., Semple, R. K., Soranzo, N., Song, K., Rocha, N., Grundberg, E., Dupuis, J., Florez, J. C., Langenberg, C., Prokopenko, I., Saxena, R., Sladek, R., Aulchenko, Y., Evans, D., Waeber, G., Erdmann, J., Burnett, M.-S., Sattar, N., Devaney, J., Willenborg, C., Hingorani, A., Witteman, J. C. M., Vollenweider, P., Glaser, B., Hengstenberg, C., Ferrucci, L., Melzer, D., Stark, K., Deanfield, J., Winogradow, J., Grassl, M., Hall, A. S., Egan, J. M., Thompson, J. R., Ricketts, S. L., König, I. R., Reinhard, W., Grundy, S., Wichmann, H.-E., Barter, P., Mahley, R., Kesaniemi, Y. A., Rader, D. J., Reilly, M. P., Epstein, S. E., Stewart, A. F. R., Van Duijn, C. M., Schunkert, H., Burling, K., Deloukas, P., Pastinen, T., Samani, N. J., McPherson, R., Davey Smith, G., Frayling, T. M., Wareham, N. J., Meigs, J. B., Mooser, V., Spector, T. D., & Consortium, G. (2009). A genome-wide association study reveals variants in ARL15 that influence adiponectin levels. PLoS Genetics, 5(12): e1000768. doi:10.1371/journal.pgen.1000768.

    Abstract

    The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P<} or =5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P{< or =0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19) for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8), n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5x10(-6), n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3), n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.
  • Timpson, N. J., Tobias, J. H., Richards, J. B., Soranzo, N., Duncan, E. L., Sims, A.-M., Whittaker, P., Kumanduri, V., Zhai, G., Glaser, B., Eisman, J., Jones, G., Nicholson, G., Prince, R., Seeman, E., Spector, T. D., Brown, M. A., Peltonen, L., Smith, G. D., Deloukas, P. and 1 moreTimpson, N. J., Tobias, J. H., Richards, J. B., Soranzo, N., Duncan, E. L., Sims, A.-M., Whittaker, P., Kumanduri, V., Zhai, G., Glaser, B., Eisman, J., Jones, G., Nicholson, G., Prince, R., Seeman, E., Spector, T. D., Brown, M. A., Peltonen, L., Smith, G. D., Deloukas, P., & Evans, D. M. (2009). Common variants in the region around Osterix are associated with bone mineral density and growth in childhood. Human Molecular Genetics, 18(8), 1510-1517. doi:10.1093/hmg/ddp052.

    Abstract

    Peak bone mass achieved in adolescence is a determinant of bone mass in later life. In order to identify genetic variants affecting bone mineral density (BMD), we performed a genome-wide association study of BMD and related traits in 1518 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). We compared results with a scan of 134 adults with high or low hip BMD. We identified associations with BMD in an area of chromosome 12 containing the Osterix (SP7) locus, a transcription factor responsible for regulating osteoblast differentiation (ALSPAC: P = 5.8 x 10(-4); Australia: P = 3.7 x 10(-4)). This region has previously shown evidence of association with adult hip and lumbar spine BMD in an Icelandic population, as well as nominal association in a UK population. A meta-analysis of these existing studies revealed strong association between SNPs in the Osterix region and adult lumbar spine BMD (P = 9.9 x 10(-11)). In light of these findings, we genotyped a further 3692 individuals from ALSPAC who had whole body BMD and confirmed the association in children as well (P = 5.4 x 10(-5)). Moreover, all SNPs were related to height in ALSPAC children, but not weight or body mass index, and when height was included as a covariate in the regression equation, the association with total body BMD was attenuated. We conclude that genetic variants in the region of Osterix are associated with BMD in children and adults probably through primary effects on growth.
  • Williams, N. M., Williams, H., Majounie, E., Norton, N., Glaser, B., Morris, H. R., Owen, M. J., & O'Donovan, M. C. (2008). Analysis of copy number variation using quantitative interspecies competitive PCR. Nucleic Acids Research, 36(17): e112. doi:10.1093/nar/gkn495.

    Abstract

    Over recent years small submicroscopic DNA copy-number variants (CNVs) have been highlighted as an important source of variation in the human genome, human phenotypic diversity and disease susceptibility. Consequently, there is a pressing need for the development of methods that allow the efficient, accurate and cheap measurement of genomic copy number polymorphisms in clinical cohorts. We have developed a simple competitive PCR based method to determine DNA copy number which uses the entire genome of a single chimpanzee as a competitor thus eliminating the requirement for competitive sequences to be synthesized for each assay. This results in the requirement for only a single reference sample for all assays and dramatically increases the potential for large numbers of loci to be analysed in multiplex. In this study we establish proof of concept by accurately detecting previously characterized mutations at the PARK2 locus and then demonstrating the potential of quantitative interspecies competitive PCR (qicPCR) to accurately genotype CNVs in association studies by analysing chromosome 22q11 deletions in a sample of previously characterized patients and normal controls.
  • Glaser, B., Nikolov, I., Chubb, D., Hamshere, M. L., Segurado, R., Moskvina, V., & Holmans, P. (2007). Analyses of single marker and pairwise effects of candidate loci for rheumatoid arthritis using logistic regression and random forests. BMC Proceedings, 1(Suppl 1): 54.

    Abstract

    Using parametric and nonparametric techniques, our study investigated the presence of single locus and pairwise effects between 20 markers of the Genetic Analysis Workshop 15 (GAW15) North American Rheumatoid Arthritis Consortium (NARAC) candidate gene data set (Problem 2), analyzing 463 independent patients and 855 controls. Specifically, our work examined the correspondence between logistic regression (LR) analysis of single-locus and pairwise interaction effects, and random forest (RF) single and joint importance measures. For this comparison, we selected small but stable RFs (500 trees), which showed strong correlations (r~0.98) between their importance measures and those by RFs grown on 5000 trees. Both RF importance measures captured most of the LR single-locus and pairwise interaction effects, while joint importance measures also corresponded to full LR models containing main and interaction effects. We furthermore showed that RF measures were particularly sensitive to data imputation. The most consistent pairwise effect on rheumatoid arthritis was found between two markers within MAP3K7IP2/SUMO4 on 6q25.1, although LR and RFs assigned different significance levels. Within a hypothetical two-stage design, pairwise LR analysis of all markers with significant RF single importance would have reduced the number of possible combinations in our small data set by 61%, whereas joint importance measures would have been less efficient for marker pair reduction. This suggests that RF single importance measures, which are able to detect a wide range of interaction effects and are computationally very efficient, might be exploited as pre-screening tool for larger association studies. Follow-up analysis, such as by LR, is required since RFs do not indicate highrisk genotype combinations.
  • Hamshere, M. L., Segurado, R., Moskvina, V., Nikolov, I., Glaser, B., & Holmans, P. A. (2007). Large-scale linkage analysis of 1302 affected relative pairs with rheumatoid arthritis. BMC Proceedings, 1 (Suppl 1), S100.

    Abstract

    Rheumatoid arthritis is the most common systematic autoimmune disease and its etiology is believed to have both strong genetic and environmental components. We demonstrate the utility of including genetic and clinical phenotypes as covariates within a linkage analysis framework to search for rheumatoid arthritis susceptibility loci. The raw genotypes of 1302 affected relative pairs were combined from four large family-based samples (North American Rheumatoid Arthritis Consortium, United Kingdom, European Consortium on Rheumatoid Arthritis Families, and Canada). The familiality of the clinical phenotypes was assessed. The affected relative pairs were subjected to autosomal multipoint affected relative-pair linkage analysis. Covariates were included in the linkage analysis to take account of heterogeneity within the sample. Evidence of familiality was observed with age at onset (p <} 0.001) and rheumatoid factor (RF) IgM (p {< 0.001), but not definite erosions (p = 0.21). Genome-wide significant evidence for linkage was observed on chromosome 6. Genome-wide suggestive evidence for linkage was observed on chromosomes 13 and 20 when conditioning on age at onset, chromosome 15 conditional on gender, and chromosome 19 conditional on RF IgM after allowing for multiple testing of covariates.
  • Segurado, R., Hamshere, M. L., Glaser, B., Nikolov, I., Moskvina, V., & Holmans, P. A. (2007). Combining linkage data sets for meta-analysis and mega-analysis: the GAW15 rheumatoid arthritis data set. BMC Proceedings, 1(Suppl 1): S104.

    Abstract

    We have used the genome-wide marker genotypes from Genetic Analysis Workshop 15 Problem 2 to explore joint evidence for genetic linkage to rheumatoid arthritis across several samples. The data consisted of four high-density genome scans on samples selected for rheumatoid arthritis. We cleaned the data, removed intermarker linkage disequilibrium, and assembled the samples onto a common genetic map using genome sequence positions as a reference for map interpolation. The individual studies were combined first at the genotype level (mega-analysis) prior to a multipoint linkage analysis on the combined sample, and second using the genome scan meta-analysis method after linkage analysis of each sample. The two approaches were compared, and give strong support to the HLA locus on chromosome 6 as a susceptibility locus. Other regions of interest include loci on chromosomes 11, 2, and 12.
  • Ziegler, A., DeStefano, A. L., König, I. R., Bardel, C., Brinza, D., Bull, S., Cai, Z., Glaser, B., Jiang, W., Lee, K. E., Li, C. X., Li, J., Li, X., Majoram, P., Meng, Y., Nicodemus, K. K., Platt, A., Schwarz, D. F., Shi, W., Shugart, Y. Y. and 7 moreZiegler, A., DeStefano, A. L., König, I. R., Bardel, C., Brinza, D., Bull, S., Cai, Z., Glaser, B., Jiang, W., Lee, K. E., Li, C. X., Li, J., Li, X., Majoram, P., Meng, Y., Nicodemus, K. K., Platt, A., Schwarz, D. F., Shi, W., Shugart, Y. Y., Stassen, H. H., Sun, Y. V., Won, S., Wang, W., Wahba, G., Zagaar, U. A., & Zhao, Z. (2007). Data mining, neural nets, trees–problems 2 and 3 of Genetic Analysis Workshop 15. Genetic Epidemiology, 31(Suppl 1), S51-S60. doi:10.1002/gepi.20280.

    Abstract

    Genome-wide association studies using thousands to hundreds of thousands of single nucleotide polymorphism (SNP) markers and region-wide association studies using a dense panel of SNPs are already in use to identify disease susceptibility genes and to predict disease risk in individuals. Because these tasks become increasingly important, three different data sets were provided for the Genetic Analysis Workshop 15, thus allowing examination of various novel and existing data mining methods for both classification and identification of disease susceptibility genes, gene by gene or gene by environment interaction. The approach most often applied in this presentation group was random forests because of its simplicity, elegance, and robustness. It was used for prediction and for screening for interesting SNPs in a first step. The logistic tree with unbiased selection approach appeared to be an interesting alternative to efficiently select interesting SNPs. Machine learning, specifically ensemble methods, might be useful as pre-screening tools for large-scale association studies because they can be less prone to overfitting, can be less computer processor time intensive, can easily include pair-wise and higher-order interactions compared with standard statistical approaches and can also have a high capability for classification. However, improved implementations that are able to deal with hundreds of thousands of SNPs at a time are required.

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