Clyde Francks

Publications

Displaying 1 - 93 of 93
  • Carrion Castillo, A., Pepe, A., Kong, X., Fisher, S. E., Mazoyer, B., Tzourio-Mazoyer, N., Crivello, F., & Francks, C. (2020). Genetic effects on planum temporale asymmetry and their limited relevance to neurodevelopmental disorders, intelligence or educational attainment. Cortex, 124, 137-153. doi:10.1016/j.cortex.2019.11.006.

    Abstract

    Previous studies have suggested that altered asymmetry of the planum temporale (PT) is associated with neurodevelopmental disorders, including dyslexia, schizophrenia, and autism. Shared genetic factors have been suggested to link PT asymmetry to these disorders. In a dataset of unrelated subjects from the general population (UK Biobank, N= 18,057), we found that PT volume asymmetry had a significant heritability of roughly 14%. In genome-wide association analysis, two loci were significantly associated with PT asymmetry, including a coding polymorphism within the gene ITIH5 that is predicted to affect the protein’s function and to be deleterious (rs41298373, P=2.01×10−15), and a locus that affects the expression of the genes BOK and DTYMK (rs7420166, P=7.54×10-10). DTYMK showed left-right asymmetry of mRNA expression in post mortem PT tissue. Cortex-wide mapping of these SNP effects revealed influences on asymmetry that went somewhat beyond the PT. Using publicly available genome-wide association statistics from large-scale studies, we saw no significant genetic correlations of PT asymmetry with autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, educational attainment or intelligence. Of the top two individual loci associated with PT asymmetry, rs41298373 showed a tentative association with intelligence (unadjusted P=0.025), while the locus at BOK/DTYMK showed tentative association with educational attainment (unadjusted Ps<0.05). These findings provide novel insights into the genetic contributions to human brain asymmetry, but do not support a substantial polygenic association of PT asymmetry with cognitive variation and mental disorders, as far as can be discerned with current sample sizes.

    Supplementary material

    Supplementary data
  • Kong, X., Tzourio-Mazoyer, N., Joliot, M., Fedorenko, E., Liu, J., Fisher, S. E., & Francks, C. (2020). Gene expression correlates of the cortical network underlying sentence processing. Neurobiology of Language. Advance publication. doi:10.1162/nol_a_00004.

    Abstract

    A pivotal question in modern neuroscience is which genes regulate brain circuits that underlie cognitive functions. However, the field is still in its infancy. Here we report an integrated investigation of the high-level language network (i.e., sentence processing network) in the human cerebral cortex, combining regional gene expression profiles, task fMRI, large-scale neuroimaging meta-analysis, and resting-state functional network approaches. We revealed reliable gene expression-functional network correlations using three different network definition strategies, and identified a consensus set of genes related to connectivity within the sentence-processing network. The genes involved showed enrichment for neural development and actin-related functions, as well as association signals with autism, which can involve disrupted language functioning. Our findings help elucidate the molecular basis of the brain’s infrastructure for language. The integrative approach described here will be useful to study other complex cognitive traits.
  • Carrion Castillo, A., Van der Haegen, L., Tzourio-Mazoyer, N., Kavaklioglu, T., Badillo, S., Chavent, M., Saracco, J., Brysbaert, M., Fisher, S. E., Mazoyer, B., & Francks, C. (2019). Genome sequencing for rightward hemispheric language dominance. Genes, Brain and Behavior. Advance online publication. doi:10.1111/gbb.12572.

    Abstract

    Most people have left‐hemisphere dominance for various aspects of language processing, but only roughly 1% of the adult population has atypically reversed, rightward hemispheric language dominance (RHLD). The genetic‐developmental program that underlies leftward language laterality is unknown, as are the causes of atypical variation. We performed an exploratory whole‐genome‐sequencing study, with the hypothesis that strongly penetrant, rare genetic mutations might sometimes be involved in RHLD. This was by analogy with situs inversus of the visceral organs (left‐right mirror reversal of the heart, lungs and so on), which is sometimes due to monogenic mutations. The genomes of 33 subjects with RHLD were sequenced and analyzed with reference to large population‐genetic data sets, as well as 34 subjects (14 left‐handed) with typical language laterality. The sample was powered to detect rare, highly penetrant, monogenic effects if they would be present in at least 10 of the 33 RHLD cases and no controls, but no individual genes had mutations in more than five RHLD cases while being un‐mutated in controls. A hypothesis derived from invertebrate mechanisms of left‐right axis formation led to the detection of an increased mutation load, in RHLD subjects, within genes involved with the actin cytoskeleton. The latter finding offers a first, tentative insight into molecular genetic influences on hemispheric language dominance.

    Supplementary material

    gbb12572-sup-0001-AppendixS1.docx
  • Eising, E., Carrion Castillo, A., Vino, A., Strand, E. A., Jakielski, K. J., Scerri, T. S., Hildebrand, M. S., Webster, R., Ma, A., Mazoyer, B., Francks, C., Bahlo, M., Scheffer, I. E., Morgan, A. T., Shriberg, L. D., & Fisher, S. E. (2019). A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development. Molecular Psychiatry, 24, 1065-1078. doi:10.1038/s41380-018-0020-x.

    Abstract

    Genetic investigations of people with impaired development of spoken language provide windows into key aspects of human biology. Over 15 years after FOXP2 was identified, most speech and language impairments remain unexplained at the molecular level. We sequenced whole genomes of nineteen unrelated individuals diagnosed with childhood apraxia of speech, a rare disorder enriched for causative mutations of large effect. Where DNA was available from unaffected parents, we discovered de novo mutations, implicating genes, including CHD3, SETD1A and WDR5. In other probands, we identified novel loss-of-function variants affecting KAT6A, SETBP1, ZFHX4, TNRC6B and MKL2, regulatory genes with links to neurodevelopment. Several of the new candidates interact with each other or with known speech-related genes. Moreover, they show significant clustering within a single co-expression module of genes highly expressed during early human brain development. This study highlights gene regulatory pathways in the developing brain that may contribute to acquisition of proficient speech.

    Supplementary material

    Eising_etal_2018sup.pdf
  • Francks, C. (2019). In search of the biological roots of typical and atypical human brain asymmetry. Physics of Life Reviews, 30, 22-24. doi:10.1016/j.plrev.2019.07.004.
  • Francks, C. (2019). The genetic bases of brain lateralization. In P. Hagoort (Ed.), Human language: From genes and brain to behavior (pp. 595-608). Cambridge, MA: MIT Press.
  • 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.
  • Kong, X., Boedhoe, P. S. W., Abe, Y., Alonso, P., Ameis, S. H., Arnold, P. D., Assogna, F., Baker, J. T., Batistuzzo, M. C., Benedetti, F., Beucke, J. C., Bollettini, I., Bose, A., Brem, S., Brennan, B. P., Buitelaar, J., Calvo, R., Cheng, Y., Cho, K. I. K., Dallaspezia, S. and 71 moreKong, X., Boedhoe, P. S. W., Abe, Y., Alonso, P., Ameis, S. H., Arnold, P. D., Assogna, F., Baker, J. T., Batistuzzo, M. C., Benedetti, F., Beucke, J. C., Bollettini, I., Bose, A., Brem, S., Brennan, B. P., Buitelaar, J., Calvo, R., Cheng, Y., Cho, K. I. K., Dallaspezia, S., Denys, D., Ely, B. A., Feusner, J., Fitzgerald, K. D., Fouche, J.-P., Fridgeirsson, E. A., Glahn, D. C., Gruner, P., Gürsel, D. A., Hauser, T. U., Hirano, Y., Hoexter, M. Q., Hu, H., Huyser, C., James, A., Jaspers-Fayer, F., Kathmann, N., Kaufmann, C., Koch, K., Kuno, M., Kvale, G., Kwon, J. S., Lazaro, L., Liu, Y., Lochner, C., Marques, P., Marsh, R., Martínez-Zalacaín, I., Mataix-Cols, D., Medland, S. E., Menchón, J. M., Minuzzi, L., Moreira, P. S., Morer, A., Morgado, P., Nakagawa, A., Nakamae, T., Nakao, T., Narayanaswamy, J. C., Nurmi, E. L., O'Neill, J., Pariente, J. C., Perriello, C., Piacentini, J., Piras, F., Piras, F., Pittenger, C., Reddy, Y. J., Rus-Oswald, O. G., Sakai, Y., Sato, J. R., Schmaal, L., Simpson, H. B., Soreni, N., Soriano-Mas, C., Spalletta, G., Stern, E. R., Stevens, M. C., Stewart, S. E., Szeszko, P. R., Tolin, D. F., Tsuchiyagaito, A., Van Rooij, D., Van Wingen, G. A., Venkatasubramanian, G., Wang, Z., Yun, J.-Y., ENIGMA-OCD Working Group, Thompson, P. M., Stein, D. J., Van den Heuvel, O. A., & Francks, C. (2019). Mapping cortical and subcortical asymmetry in obsessive-compulsive disorder: Findings from the ENIGMA Consortium. Biological Psychiatry. Advance online publication. doi:10.1016/j.biopsych.2019.04.022.

    Abstract

    Objective Lateralized dysfunction has been suggested in Obsessive-Compulsive Disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of structural brain asymmetry. Here we carried out by far the largest study of brain structural asymmetry in OCD. Method We studied a collection of 16 pediatric datasets (501 OCD patients and 439 healthy controls), as well as 30 adult datasets (1777 patients and 1654 controls) from the OCD Working Group within the ENIGMA (Enhancing Neuro-Imaging Genetics through Meta-Analysis) consortium. Asymmetries of the volumes of subcortical structures, and of regional cortical thickness and surface area measures, were assessed based on T1-weighted MRI scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in OCD patients. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status. Results In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen’s d = 0.19) and the pallidum (less leftward; d = -0.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, and/or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets. Conclusions The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD.
  • De Kovel, C. G. F., Aftanas, L., Aleman, A., Alexander-Bloch, A. F., Baune, B. T., Brack, I., Bülow, R., Filho, G. B., Carballedo, A., Connolly, C. G., Cullen, K. R., Dannlowski, U., Davey, C. G., Dima, D., Dohm, K., Erwin-Grabner, T., Frodl, T., Fu, C. H., Hall, G. B., Glahn, D. C. and 58 moreDe Kovel, C. G. F., Aftanas, L., Aleman, A., Alexander-Bloch, A. F., Baune, B. T., Brack, I., Bülow, R., Filho, G. B., Carballedo, A., Connolly, C. G., Cullen, K. R., Dannlowski, U., Davey, C. G., Dima, D., Dohm, K., Erwin-Grabner, T., Frodl, T., Fu, C. H., Hall, G. B., Glahn, D. C., Godlewska, B., Gotlib, I. H., Goya-Maldonado, R., Grabe, H. J., Groenewold, N. A., Grotegerd, D., Gruber, O., Harris, M. A., Harrison, B. J., Hatton, S. N., Hickie, I. B., Ho, T. C., Jahanshad, N., Kircher, T., Krämer, B., Krug, A., Lagopoulos, J., Leehr, E. J., Li, M., MacMaster, F. P., MacQueen, G., McIntosh, A. M., McLellan, Q., Medland, S. E., Mueller, B. A., Nenadic, I., Osipov, E., Papmeyer, M., Portella, M. J., Reneman, L., Rosa, P. G., Sacchet, M. D., Schnell, K., Schrantee, A., Sim, K., Simulionyte, E., Sindermann, L., Singh, A., Stein, D. J., Ubani, B. N., der Wee, N. J. V., der Werff, S. J. V., Veer, I. M., Vives-Gilabert, Y., Völzke, H., Walter, H., Walter, M., Schreiner, M. W., Whalley, H., Winter, N., Wittfeld, K., Yang, T. T., Yüksel, D., Zaremba, D., Thompson, P. M., Veltman, D. J., Schmaal, L., & Francks, C. (2019). No alterations of brain structural asymmetry in major depressive disorder: An ENIGMA consortium analysis. American Journal of Psychiatry, 176(12), 1039-1049. doi:10.1176/appi.ajp.2019.18101144.

    Abstract

    Objective: Asymmetry is a subtle but pervasive aspect of the human brain, and it may be altered in several psychiatric conditions. MRI studies have shown subtle differences of brain anatomy between people with major depressive disorder and healthy control subjects, but few studies have specifically examined brain anatomical asymmetry in relation to this disorder, and results from those studies have remained inconclusive. At the functional level, some electroencephalography studies have indicated left fronto-cortical hypoactivity and right parietal hypoactivity in depressive disorders, so aspects of lateralized anatomy may also be affected. The authors used pooled individual-level data from data sets collected around the world to investigate differences in laterality in measures of cortical thickness, cortical surface area, and subcortical volume between individuals with major depression and healthy control subjects. Methods: The authors investigated differences in the laterality of thickness and surface area measures of 34 cerebral cortical regions in 2,256 individuals with major depression and 3,504 control subjects from 31 separate data sets, and they investigated volume asymmetries of eight subcortical structures in 2,540 individuals with major depression and 4,230 control subjects from 32 data sets. T1-weighted MRI data were processed with a single protocol using FreeSurfer and the Desikan-Killiany atlas. The large sample size provided 80% power to detect effects of the order of Cohen’s d=0.1. Results: The largest effect size (Cohen’s d) of major depression diagnosis was 0.085 for the thickness asymmetry of the superior temporal cortex, which was not significant after adjustment for multiple testing. Asymmetry measures were not significantly associated with medication use, acute compared with remitted status, first episode compared with recurrent status, or age at onset. Conclusions: Altered brain macro-anatomical asymmetry may be of little relevance to major depression etiology in most cases.
  • De Kovel, C. G. F., & Francks, C. (2019). The molecular genetics of hand preference revisited. Scientific Reports, 9: 5986. doi:10.1038/s41598-019-42515-0.

    Abstract

    Hand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we performed a genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N = 331,037). We used gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence supporting any of the previously suggested variants or genes, nor that genes involved in visceral laterality have a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Our analysis did produce a small number of novel, significant associations, including one implicating the microtubule-associated gene MAP2 in handedness.
  • De Kovel, C. G. F., Carrion Castillo, A., & Francks, C. (2019). A large-scale population study of early life factors influencing left-handedness. Scientific Reports, 9: 584. doi:10.1038/s41598-018-37423-8.

    Abstract

    Hand preference is a conspicuous variation in human behaviour, with a worldwide proportion of around 90% of people preferring to use the right hand for many tasks, and 10% the left hand. We used the large cohort of the UK biobank (~500,000 participants) to study possible relations between early life factors and adult hand preference. The probability of being left-handed was affected by the year and location of birth, likely due to cultural effects. In addition, hand preference was affected by birthweight, being part of a multiple birth, season of birth, breastfeeding, and sex, with each effect remaining significant after accounting for all others. Analysis of genome-wide genotype data showed that left-handedness was very weakly heritable, but shared no genetic basis with birthweight. Although on average left-handers and right-handers differed for a number of early life factors, all together these factors had only a minimal predictive value for individual hand preference.

    Supplementary material

    Supplementary information
  • Postema, M., Van Rooij, D., Anagnostou, E., Arango, C., Auzias, G., Behrmann, M., Busatto Filho, G., Calderoni, S., Calvo, R., Daly, E., Deruelle, C., Di Martino, A., Dinstein, I., Duran, F. L. S., Durston, S., Ecker, C., Ehrlich, S., Fair, D., Fedor, J., Feng, X. and 38 morePostema, M., Van Rooij, D., Anagnostou, E., Arango, C., Auzias, G., Behrmann, M., Busatto Filho, G., Calderoni, S., Calvo, R., Daly, E., Deruelle, C., Di Martino, A., Dinstein, I., Duran, F. L. S., Durston, S., Ecker, C., Ehrlich, S., Fair, D., Fedor, J., Feng, X., Fitzgerald, J., Floris, D. L., Freitag, C. M., Gallagher, L., Glahn, D. C., Gori, I., Haar, S., Hoekstra, L., Jahanshad, N., Jalbrzikowski, M., Janssen, J., King, J. A., Kong, X., Lazaro, L., Lerch, J. P., Luna, B., Martinho, M. M., McGrath, J., Medland, S. E., Muratori, F., Murphy, C. M., Murphy, D. G. M., O'Hearn, K., Oranje, B., Parellada, M., Puig, O., Retico, A., Rosa, P., Rubia, K., Shook, D., Taylor, M., Tosetti, M., Wallace, G. L., Zhou, F., Thompson, P., Fisher, S. E., Buitelaar, J. K., & Francks, C. (2019). Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets. Nature Communications, 10: 4958. doi:10.1038/s41467-019-13005-8.

    Supplementary material

    Supplementary Information
  • Satizabal, C. L., Adams, H. H. H., Hibar, D. P., White, C. C., Knol, M. J., Stein, J. L., Scholz, M., Sargurupremraj, M., Jahanshad, N., Roshchupkin, G. V., Smith, A. V., Bis, J. C., Jian, X., Luciano, M., Hofer, E., Teumer, A., Van der Lee, S. J., Yang, J., Yanek, L. R., Lee, T. V. and 271 moreSatizabal, C. L., Adams, H. H. H., Hibar, D. P., White, C. C., Knol, M. J., Stein, J. L., Scholz, M., Sargurupremraj, M., Jahanshad, N., Roshchupkin, G. V., Smith, A. V., Bis, J. C., Jian, X., Luciano, M., Hofer, E., Teumer, A., Van der Lee, S. J., Yang, J., Yanek, L. R., Lee, T. V., Li, S., Hu, Y., Koh, J. Y., Eicher, J. D., Desrivières, S., Arias-Vasquez, A., Chauhan, G., Athanasiu, L., Renteria, M. E., Kim, S., Höhn, D., Armstrong, N. J., Chen, Q., Holmes, A. J., Den Braber, A., Kloszewska, I., Andersson, M., Espeseth, T., Grimm, O., Abramovic, L., Alhusaini, S., Milaneschi, Y., Papmeyer, M., Axelsson, T., Ehrlich, S., Roiz-Santiañez, R., Kraemer, B., Håberg, A. K., Jones, H. J., Pike, G. B., Stein, D. J., Stevens, A., Bralten, J., Vernooij, M. W., Harris, T. B., Filippi, I., Witte, A. V., Guadalupe, T., Wittfeld, K., Mosley, T. H., Becker, J. T., Doan, N. T., Hagenaars, S. P., Saba, Y., Cuellar-Partida, G., Amin, N., Hilal, S., Nho, K., Karbalai, N., Arfanakis, K., Becker, D. M., Ames, D., Goldman, A. L., Lee, P. H., Boomsma, D. I., Lovestone, S., Giddaluru, S., Le Hellard, S., Mattheisen, M., Bohlken, M. M., Kasperaviciute, D., Schmaal, L., Lawrie, S. M., Agartz, I., Walton, E., Tordesillas-Gutierrez, D., Davies, G. E., Shin, J., Ipser, J. C., Vinke, L. N., Hoogman, M., Jia, T., Burkhardt, R., Klein, M., Crivello, F., Janowitz, D., Carmichael, O., Haukvik, U. K., Aribisala, B. S., Schmidt, H., Strike, L. T., Cheng, C.-Y., Risacher, S. L., Pütz, B., Fleischman, D. A., Assareh, A. A., Mattay, V. S., Buckner, R. L., Mecocci, P., Dale, A. M., Cichon, S., Boks, M. P., Matarin, M., Penninx, B. W. J. H., Calhoun, V. D., Chakravarty, M. M., Marquand, A., Macare, C., Masouleh, S. K., Oosterlaan, J., Amouyel, P., Hegenscheid, K., Rotter, J. I., Schork, A. J., Liewald, D. C. M., De Zubicaray, G. I., Wong, T. Y., Shen, L., Sämann, P. G., Brodaty, H., Roffman, J. L., De Geus, E. J. C., Tsolaki, M., Erk, S., Van Eijk, K. R., Cavalleri, G. L., Van der Wee, N. J. A., McIntosh, A. M., Gollub, R. L., Bulayeva, K. B., Bernard, M., Richards, J. S., Himali, J. J., Loeffler, M., Rommelse, N., Hoffmann, W., Westlye, L. T., Valdés Hernández, M. C., Hansell, N. K., Van Erp, T. G. M., Wolf, C., Kwok, J. B. J., Vellas, B., Heinz, A., Olde Loohuis, L. M., Delanty, N., Ho, B.-C., Ching, C. R. K., Shumskaya, E., Singh, B., Hofman, A., Van der Meer, D., Homuth, G., Psaty, B. M., Bastin, M., Montgomery, G. W., Foroud, T. M., Reppermund, S., Hottenga, J.-J., Simmons, A., Meyer-Lindenberg, A., Cahn, W., Whelan, C. D., Van Donkelaar, M. M. J., Yang, Q., Hosten, N., Green, R. C., Thalamuthu, A., Mohnke, S., Hulshoff Pol, H. E., Lin, H., Jack Jr., C. R., Schofield, P. R., Mühleisen, T. W., Maillard, P., Potkin, S. G., Wen, W., Fletcher, E., Toga, A. W., Gruber, O., Huentelman, M., Smith, G. D., Launer, L. J., Nyberg, L., Jönsson, E. G., Crespo-Facorro, B., Koen, N., Greve, D., Uitterlinden, A. G., Weinberger, D. R., Steen, V. M., Fedko, I. O., Groenewold, N. A., Niessen, W. J., Toro, R., Tzourio, C., Longstreth Jr., W. T., Ikram, M. K., Smoller, J. W., Van Tol, M.-J., Sussmann, J. E., Paus, T., Lemaître, H., Schroeter, M. L., Mazoyer, B., Andreassen, O. A., Holsboer, F., Depondt, C., Veltman, D. J., Turner, J. A., Pausova, Z., Schumann, G., Van Rooij, D., Djurovic, S., Deary, I. J., McMahon, K. L., Müller-Myhsok, B., Brouwer, R. M., Soininen, H., Pandolfo, M., Wassink, T. H., Cheung, J. W., Wolfers, T., Martinot, J.-L., Zwiers, M. P., Nauck, M., Melle, I., Martin, N. G., Kanai, R., Westman, E., Kahn, R. S., Sisodiya, S. M., White, T., Saremi, A., Van Bokhoven, H., Brunner, H. G., Völzke, H., Wright, M. J., Van 't Ent, D., Nöthen, M. M., Ophoff, R. A., Buitelaar, J. K., Fernández, G., Sachdev, P. S., Rietschel, M., Van Haren, N. E. M., Fisher, S. E., Beiser, A. S., Francks, C., Saykin, A. J., Mather, K. A., Romanczuk-Seiferth, N., Hartman, C. A., DeStefano, A. L., Heslenfeld, D. J., Weiner, M. W., Walter, H., Hoekstra, P. J., Nyquist, P. A., Franke, B., Bennett, D. A., Grabe, H. J., Johnson, A. D., Chen, C., Van Duijn, C. M., Lopez, O. L., Fornage, M., Wardlaw, J. A., Schmidt, R., DeCarli, C., De Jager, P. L., Villringer, A., Debette, S., Gudnason, V., Medland, S. E., Shulman, J. M., Thompson, P. M., Seshadri, S., & Ikram, M. A. (2019). Genetic architecture of subcortical brain structures in 38,854 individuals worldwide. Nature Genetics, 51, 1624-1636. doi:10.1038/s41588-019-0511-y.

    Abstract

    Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
  • Truong, D. T., Adams, A. K., Paniagua, S., Frijters, J. C., Boada, R., Hill, D. E., Lovett, M. W., Mahone, E. M., Willcutt, E. G., Wolf, M., Defries, J. C., Gialluisi, A., Francks, C., Fisher, S. E., Olson, R. K., Pennington, B. F., Smith, S. D., Bosson-Heenan, J., & Gruen, J. R. (2019). Multivariate genome-wide association study of rapid automatised naming and rapid alternating stimulus in Hispanic American and African–American youth. Journal of Medical Genetics, 56(8), 557-566. doi:10.1136/jmedgenet-2018-105874.

    Abstract

    Background Rapid automatised naming (RAN) and rapid alternating stimulus (RAS) are reliable predictors of reading disability. The underlying biology of reading disability is poorly understood. However, the high correlation among RAN, RAS and reading could be attributable to shared genetic factors that contribute to common biological mechanisms. Objective To identify shared genetic factors that contribute to RAN and RAS performance using a multivariate approach. Methods We conducted a multivariate genome-wide association analysis of RAN Objects, RAN Letters and RAS Letters/Numbers in a sample of 1331 Hispanic American and African–American youth. Follow-up neuroimaging genetic analysis of cortical regions associated with reading ability in an independent sample and epigenetic examination of extant data predicting tissue-specific functionality in the brain were also conducted. Results Genome-wide significant effects were observed at rs1555839 (p=4.03×10−8) and replicated in an independent sample of 318 children of European ancestry. Epigenetic analysis and chromatin state models of the implicated 70 kb region of 10q23.31 support active transcription of the gene RNLS in the brain, which encodes a catecholamine metabolising protein. Chromatin contact maps of adult hippocampal tissue indicate a potential enhancer–promoter interaction regulating RNLS expression. Neuroimaging genetic analysis in an independent, multiethnic sample (n=690) showed that rs1555839 is associated with structural variation in the right inferior parietal lobule. Conclusion This study provides support for a novel trait locus at chromosome 10q23.31 and proposes a potential gene–brain–behaviour relationship for targeted future functional analysis to understand underlying biological mechanisms for reading disability.

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  • Devanna, P., Chen, X. S., Ho, J., Gajewski, D., Smith, S. D., Gialluisi, A., Francks, C., Fisher, S. E., Newbury, D. F., & Vernes, S. C. (2018). Next-gen sequencing identifies non-coding variation disrupting miRNA binding sites in neurological disorders. Molecular Psychiatry, 23(5), 1375-1384. doi:10.1038/mp.2017.30.

    Abstract

    Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large-scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome is likely to play an important role in these phenotypes. Herein we show the importance of 3 prime untranslated region (3'UTR) non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from next generation sequencing (NGS) data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant and the affected gene (ARHGEF39) represent new putative risk factors for SLI. Furthermore, we identified 3′UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease

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    mp201730x1.docx
  • Kong, X., Mathias, S. R., Guadalupe, T., ENIGMA Laterality Working Group, Glahn, D. C., Franke, B., Crivello, F., Tzourio-Mazoyer, N., Fisher, S. E., Thompson, P. M., & Francks, C. (2018). Mapping Cortical Brain Asymmetry in 17,141 Healthy Individuals Worldwide via the ENIGMA Consortium. Proceedings of the National Academy of Sciences of the United States of America, 115(22), E5154-E5163. doi:10.1073/pnas.1718418115.

    Abstract

    Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here the ENIGMA consortium presents the largest ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and intracranial volume. Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (N = 1,443 and 1,113, respectively), we found several asymmetries showing significant, replicable heritability. The structural asymmetries identified, and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.

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    pnas.1718418115.sapp.pdf
  • De Kovel, C. G. F., Lisgo, S. N., Fisher, S. E., & Francks, C. (2018). Subtle left-right asymmetry of gene expression profiles in embryonic and foetal human brains. Scientific Reports, 8: 12606. doi:10.1038/s41598-018-29496-2.

    Abstract

    Left-right laterality is an important aspect of human –and in fact all vertebrate– brain organization for which the genetic basis is poorly understood. Using RNA sequencing data we contrasted gene expression in left- and right-sided samples from several structures of the anterior central nervous systems of post mortem human embryos and foetuses. While few individual genes stood out as significantly lateralized, most structures showed evidence of laterality of their overall transcriptomic profiles. These left-right differences showed overlap with age-dependent changes in expression, indicating lateralized maturation rates, but not consistently in left-right orientation over all structures. Brain asymmetry may therefore originate in multiple locations, or if there is a single origin, it is earlier than 5 weeks post conception, with structure-specific lateralized processes already underway by this age. This pattern is broadly consistent with the weak correlations reported between various aspects of adult brain laterality, such as language dominance and handedness.
  • De Kovel, C. G. F., Lisgo, S. N., & Francks, C. (2018). Transcriptomic analysis of left-right differences in human embryonic forebrain and midbrain. Scientific Data, 5: 180164. doi:10.1038/sdata.2018.164.

    Abstract

    Left-right asymmetry is subtle but pervasive in the human central nervous system. This asymmetry is initiated early during development, but its mechanisms are poorly known. Forebrains and midbrains were dissected from six human embryos at Carnegie stages 15 or 16, one of which was female. The structures were divided into left and right sides, and RNA was isolated. RNA was sequenced with 100 base-pair paired ends using Illumina Hiseq 4000. After quality control, five paired brain sides were available for midbrain and forebrain. A paired analysis between left- and right sides of a given brain structure across the embryos identified left-right differences. The dataset, consisting of Fastq files and a read count table, can be further used to study early development of the human brain
  • Carrion Castillo, A., Maassen, B., Franke, B., Heister, A., Naber, M., Van der Leij, A., Francks, C., & Fisher, S. E. (2017). Association analysis of dyslexia candidate genes in a Dutch longitudinal sample. European Journal of Human Genetics, 25(4), 452-460. doi:10.1038/ejhg.2016.194.

    Abstract

    Dyslexia is a common specific learning disability with a substantive genetic component. Several candidate genes have been proposed to be implicated in dyslexia susceptibility, such as DYX1C1, ROBO1, KIAA0319, and DCDC2. Associations with variants in these genes have also been reported with a variety of psychometric measures tapping into the underlying processes that might be impaired in dyslexic people. In this study, we first conducted a literature review to select single nucleotide polymorphisms (SNPs) in dyslexia candidate genes that had been repeatedly implicated across studies. We then assessed the SNPs for association in the richly phenotyped longitudinal data set from the Dutch Dyslexia Program. We tested for association with several quantitative traits, including word and nonword reading fluency, rapid naming, phoneme deletion, and nonword repetition. In this, we took advantage of the longitudinal nature of the sample to examine if associations were stable across four educational time-points (from 7 to 12 years). Two SNPs in the KIAA0319 gene were nominally associated with rapid naming, and these associations were stable across different ages. Genetic association analysis with complex cognitive traits can be enriched through the use of longitudinal information on trait development.
  • Chen, X. S., Reader, R. H., Hoischen, A., Veltman, J. A., Simpson, N. H., Francks, C., Newbury, D. F., & Fisher, S. E. (2017). Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment. Scientific Reports, 7: 46105. doi:10.1038/srep46105.

    Abstract

    A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidates carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential “multiple-hit” cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affecting STARD9, while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. On broadening scope to all rare and novel variants throughout the exomes, we identified biological themes that were enriched for such variants, including microtubule transport and cytoskeletal regulation.
  • Gialluisi, A., Guadalupe, T., Francks, C., & Fisher, S. E. (2017). Neuroimaging genetic analyses of novel candidate genes associated with reading and language. Brain and Language, 172, 9-15. doi:10.1016/j.bandl.2016.07.002.

    Abstract

    Neuroimaging measures provide useful endophenotypes for tracing genetic effects on reading and language. A recent Genome-Wide Association Scan Meta-Analysis (GWASMA) of reading and language skills (N = 1862) identified strongest associations with the genes CCDC136/FLNC and RBFOX2. Here, we follow up the top findings from this GWASMA, through neuroimaging genetics in an independent sample of 1275 healthy adults. To minimize multiple-testing, we used a multivariate approach, focusing on cortical regions consistently implicated in prior literature on developmental dyslexia and language impairment. Specifically, we investigated grey matter surface area and thickness of five regions selected a priori: middle temporal gyrus (MTG); pars opercularis and pars triangularis in the inferior frontal gyrus (IFG-PO and IFG-PT); postcentral parietal gyrus (PPG) and superior temporal gyrus (STG). First, we analysed the top associated polymorphisms from the reading/language GWASMA: rs59197085 (CCDC136/FLNC) and rs5995177 (RBFOX2). There was significant multivariate association of rs5995177 with cortical thickness, driven by effects on left PPG, right MTG, right IFG (both PO and PT), and STG bilaterally. The minor allele, previously associated with reduced reading-language performance, showed negative effects on grey matter thickness. Next, we performed exploratory gene-wide analysis of CCDC136/FLNC and RBFOX2; no other associations surpassed significance thresholds. RBFOX2 encodes an important neuronal regulator of alternative splicing. Thus, the prior reported association of rs5995177 with reading/language performance could potentially be mediated by reduced thickness in associated cortical regions. In future, this hypothesis could be tested using sufficiently large samples containing both neuroimaging data and quantitative reading/language scores from the same individuals.

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  • Guadalupe, T., Mathias, S. R., Van Erp, T. G. M., Whelan, C. D., Zwiers, M. P., Abe, Y., Abramovic, L., Agartz, I., Andreassen, O. A., Arias-Vásquez, A., Aribisala, B. S., Armstrong, N. J., Arolt, V., Artiges, E., Ayesa-Arriola, R., Baboyan, V. G., Banaschewski, T., Barker, G., Bastin, M. E., Baune, B. T. and 141 moreGuadalupe, T., Mathias, S. R., Van Erp, T. G. M., Whelan, C. D., Zwiers, M. P., Abe, Y., Abramovic, L., Agartz, I., Andreassen, O. A., Arias-Vásquez, A., Aribisala, B. S., Armstrong, N. J., Arolt, V., Artiges, E., Ayesa-Arriola, R., Baboyan, V. G., Banaschewski, T., Barker, G., Bastin, M. E., Baune, B. T., Blangero, J., Bokde, A. L., Boedhoe, P. S., Bose, A., Brem, S., Brodaty, H., Bromberg, U., Brooks, S., Büchel, C., Buitelaar, J., Calhoun, V. D., Cannon, D. M., Cattrell, A., Cheng, Y., Conrod, P. J., Conzelmann, A., Corvin, A., Crespo-Facorro, B., Crivello, F., Dannlowski, U., De Zubicaray, G. I., De Zwarte, S. M., Deary, I. J., Desrivières, S., Doan, N. T., Donohoe, G., Dørum, E. S., Ehrlich, S., Espeseth, T., Fernández, G., Flor, H., Fouche, J.-P., Frouin, V., Fukunaga, M., Gallinat, J., Garavan, H., Gill, M., Suarez, A. G., Gowland, P., Grabe, H. J., Grotegerd, D., Gruber, O., Hagenaars, S., Hashimoto, R., Hauser, T. U., Heinz, A., Hibar, D. P., Hoekstra, P. J., Hoogman, M., Howells, F. M., Hu, H., Hulshoff Pol, H. E.., Huyser, C., Ittermann, B., Jahanshad, N., Jönsson, E. G., Jurk, S., Kahn, R. S., Kelly, S., Kraemer, B., Kugel, H., Kwon, J. S., Lemaitre, H., Lesch, K.-P., Lochner, C., Luciano, M., Marquand, A. F., Martin, N. G., Martínez-Zalacaín, I., Martinot, J.-L., Mataix-Cols, D., Mather, K., McDonald, C., McMahon, K. L., Medland, S. E., Menchón, J. M., Morris, D. W., Mothersill, O., Maniega, S. M., Mwangi, B., Nakamae, T., Nakao, T., Narayanaswaamy, J. C., Nees, F., Nordvik, J. E., Onnink, A. M. H., Opel, N., Ophoff, R., Martinot, M.-L.-P., Orfanos, D. P., Pauli, P., Paus, T., Poustka, L., Reddy, J. Y., Renteria, M. E., Roiz-Santiáñez, R., Roos, A., Royle, N. A., Sachdev, P., Sánchez-Juan, P., Schmaal, L., Schumann, G., Shumskaya, E., Smolka, M. N., Soares, J. C., Soriano-Mas, C., Stein, D. J., Strike, L. T., Toro, R., Turner, J. A., Tzourio-Mazoyer, N., Uhlmann, A., Valdés Hernández, M., Van den Heuvel, O. A., Van der Meer, D., Van Haren, N. E.., Veltman, D. J., Venkatasubramanian, G., Vetter, N. C., Vuletic, D., Walitza, S., Walter, H., Walton, E., Wang, Z., Wardlaw, J., Wen, W., Westlye, L. T., Whelan, R., Wittfeld, K., Wolfers, T., Wright, M. J., Xu, J., Xu, X., Yun, J.-Y., Zhao, J., Franke, B., Thompson, P. M., Glahn, D. C., Mazoyer, B., Fisher, S. E., & Francks, C. (2017). Human subcortical asymmetries in 15,847 people worldwide reveal effects of age and sex. Brain Imaging and Behavior, 11(5), 1497-1514. doi:10.1007/s11682-016-9629-z.

    Abstract

    The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.

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    11682_2016_9629_MOESM1_ESM.pdf
  • Hibar, D. P., Adams, H. H. H., Jahanshad, N., Chauhan, G., Stein, J. L., Hofer, E., Rentería, M. E., Bis, J. C., Arias-Vasquez, A., Ikram, M. K., Desrivieres, S., Vernooij, M. W., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K., Aribisala, B. S., Armstrong, N. J., Athanasiu, L. and 312 moreHibar, D. P., Adams, H. H. H., Jahanshad, N., Chauhan, G., Stein, J. L., Hofer, E., Rentería, M. E., Bis, J. C., Arias-Vasquez, A., Ikram, M. K., Desrivieres, S., Vernooij, M. W., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K., Aribisala, B. S., Armstrong, N. J., Athanasiu, L., Axelsson, T., Beecham, A. H., Beiser, A., Bernard, M., Blanton, S. H., Bohlken, M. M., Boks, M. P., Bralten, J., Brickman, A. M., Carmichael, O., Chakravarty, M. M., Chen, Q., Ching, C. R. K., Chouraki, V., Cuellar-Partida, G., Crivello, F., den Brabander, A., Doan, N. T., Ehrlich, S., Giddaluru, S., Goldman, A. L., Gottesman, R. F., Grimm, O., Griswold, M. E., Guadalupe, T., Gutman, B. A., Hass, J., Haukvik, U. K., Hoehn, D., Holmes, A. J., Hoogman, M., Janowitz, D., Jia, T., Jørgensen, K. N., Mirza-Schreiber, N., Kasperaviciute, D., Kim, S., Klein, M., Krämer, B., Lee, P. H., Liewald, D. C. M., Lopez, L. M., Luciano, M., Macare, C., Marquand, A. F., Matarin, M., Mather, K. A., Mattheisen, M., McKay, D. R., Milaneschi, Y., Maniega, S. M., Nho, K., Nugent, A. C., Nyquist, P., Olde Loohuis, L. M., Oosterlaan, J., Papmeyer, M., Pirpamer, L., Pütz, B., Ramasamy, A., Richards, J. S., Risacher, S., Roiz-Santiañez, R., Rommelse, N., Ropele, S., Rose, E., Royle, N. A., Rundek, T., Sämann, P. G., Saremi, A., Satizabal, C. L., Schmaal, L., Schork, A. J., Shen, L., Shin, J., Shumskaya, E., Smith, A. V., Sprooten, E., Strike, L. T., Teumer, A., Tordesillas-Gutierrez, D., Toro, R., Trabzuni, D., Trompet, S., Vaidya, D., Van der Grond, J., Van der Lee, S. J., Van der Meer, D., Van Donkelaar, M. M. J., Van Eijk, K. R., van Erp, T. G. M., Van Rooij, D., Walton, E., Westlye, L. T., Whelan, C. D., Windham, B. G., Winkler, A. M., Wittfeld, K. M., Woldehawariat, G., Wolf, C., Wolfers, T., Yanek, L. R., Yang, J., Zijdenbos, A., Zwiers, M. P., Agartz, I., Almasy, L., Ames, D., Amouyel, P., Andreassen, O. A., Arepalli, S., Assareh, A. A., Barral, S., Bastin, M. E., Becker, D. M., Becker, J. T., Bennett, D. A., Blangero, J., Van Bokhoven, H., Boomsma, D. I., Brodaty, H., Brouwer, R. M., Brunner, H. G., Buckner, R. L., Buitelaar, J. K., Bulayeva, K. B., Cahn, W., Calhoun, V. D., Cannon, D. M., Cavalleri, G. L., Cheng, C.-Y., Cichon, S., Cookson, M. R., Corvin, A., Crespo-Facorro, B., Curran, J. E., Czisch, M., Dale, A. M., Davies, G. E., De Craen, A. J. M., De Geus, E. J. C., De Jager, P. L., De Zubicaray, G. i., Deary, I. J., Debette, S., DeCarli, C., Delanty, N., Depondt, C., DeStefano, A., Dillman, A., Djurovic, S., Donohoe, G., Drevets, W. C., Duggirala, R., Dyer, T. D., Enzinger, C., Erk, S., Espeseth, T., Fedko, I. O., Fernández, G., Ferrucci, L., Fisher, S. E., Fleischman, D. A., Ford, I., Fornage, M., Foroud, T. M., Fox, P. T., Francks, C., Fukunaga, M., Gibbs, J. R., Glahn, D. C., Gollub, R. L., Göring, H. H. H., Green, R. C., Gruber, O., Gudnason, V., Guelfi, S., Haberg, A. K., Hansell, N. K., Hardy, J., Hartman, C. A., Hashimoto, R., Hegenscheid, K., Heinz, A., Le Hellard, S., Hernandez, D. G., Heslenfeld, D. J., Ho, B.-C., Hoekstra, P. J., Hoffmann, W., Hofman, A., Holsboer, F., Homuth, G., Hosten, N., Hottenga, J.-J., Huentelman, M., Pol, H. E. H., Ikeda, M., Jack Jr., C. R., Jenkinson, M., Johnson, R., Jonsson, E. G., Jukema, J. W., Kahn, R. S., Kanai, R., Kloszewska, I., Knopman, D. S., Kochunov, P., Kwok, J. B., Lawrie, S. M., Lemaître, H., Liu, X., Longo, D. L., Lopez, O. L., Lovestone, S., Martinez, O., Martinot, J.-L., Mattay, V. S., McDonald, C., Mcintosh, A. M., McMahon, F., McMahon, K. L., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Mohnke, S., Montgomery, G. W., Morris, D. W., Mosley, T. H., Mühleisen, T. W., Müller-Myhsok, B., Nalls, M. A., Nauck, M., Nichols, T. E., Niessen, W. J., Nöthen, M. M., Nyberg, L., Ohi, K., Olvera, R. L., Ophoff, R. A., Pandolfo, M., Paus, T., Pausova, Z., Penninx, B. W. J. H., Pike, G. B., Potkin, S. G., Psaty, B. M., Reppermund, S., Rietschel, M., Roffman, J. L., Romanczuk-Seiferth, N., Rotter, J. I., Ryten, M., Sacco, R. L., Sachdev, P. S., Saykin, A. J., Schmidt, R., Schmidt, H., Schofield, P. R., Sigursson, S., Simmons, A., Singleton, A., Sisodiya, S. M., Smith, C., Smoller, J. W., Soininen, H., Steen, V. M., Stott, D. J., Sussmann, J. E., Thalamuthu, A., Toga, A. W., Traynor, B. J., Troncoso, J., Tsolaki, M., Tzourio, C., Uitterlinden, A. G., Hernández, M. C. V., Van der Brug, M., Van der Lugt, A., Van der Wee, N. J. A., Van Haren, N. E. M., Van Tol, M.-J., Vardarajan, B. N., Vellas, B., Veltman, D. J., Völzke, H., Walter, H., Wardlaw, J. M., Wassink, T. H., Weale, M. e., Weinberger, D. R., Weiner, M., Wen, W., Westman, E., White, T., Wong, T. Y., Wright, C. B., Zielke, R. H., Zonderman, A. B., Martin, N. G., Van Duijn, C. M., Wright, M. J., Longstreth, W. W. T., Schumann, G., Grabe, H. J., Franke, B., Launer, L. J., Medland, S. E., Seshadri, S., Thompson, P. M., & Ikram, A. (2017). Novel genetic loci associated with hippocampal volume. Nature Communications, 8: 13624. doi:10.1038/ncomms13624.

    Abstract

    The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer’s disease (rg=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

    Supplementary material

    ncomms13624-s1.pdf ncomms13624-s2.xlsx
  • Kavaklioglu, T., Guadalupe, T., Zwiers, M., Marquand, A. F., Onnink, M., Shumskaya, E., Brunner, H., Fernandez, G., Fisher, S. E., & Francks, C. (2017). Structural asymmetries of the human cerebellum in relation to cerebral cortical asymmetries and handedness. Brain Structure and Function, 22, 1611-1623. doi:10.1007/s00429-016-1295-9.

    Abstract

    There is evidence that the human cerebellum is involved not only in motor control but also in other cognitive functions. Several studies have shown that language-related activation is lateralized toward the right cerebellar hemisphere in most people, in accordance with leftward cerebral cortical lateralization for language and a general contralaterality of cerebral–cerebellar activations. In terms of behavior, hand use elicits asymmetrical activation in the cerebellum, while hand preference is weakly associated with language lateralization. However, it is not known how, or whether, these functional relations are reflected in anatomy. We investigated volumetric gray matter asymmetries of cerebellar lobules in an MRI data set comprising 2226 subjects. We tested these cerebellar asymmetries for associations with handedness, and for correlations with cerebral cortical anatomical asymmetries of regions important for language or hand motor control, as defined by two different automated image analysis methods and brain atlases, and supplemented with extensive visual quality control. No significant associations of cerebellar asymmetries to handedness were found. Some significant associations of cerebellar lobular asymmetries to cerebral cortical asymmetries were found, but none of these correlations were greater than 0.14, and they were mostly method-/atlas-dependent. On the basis of this large and highly powered study, we conclude that there is no overt structural manifestation of cerebellar functional lateralization and connectivity, in respect of hand motor control or language laterality
  • De Kovel, C. G. F., Lisgo, S., Karlebach, G., Ju, J., Cheng, G., Fisher, S. E., & Francks, C. (2017). Left-right asymmetry of maturation rates in human embryonic neural development. Biological Psychiatry, 82(3), 204-212. doi:10.1016/j.biopsych.2017.01.016.

    Abstract

    Background Left-right asymmetry is a fundamental organizing feature of the human brain, and neuro-psychiatric disorders such as schizophrenia sometimes involve alterations of brain asymmetry. As early as 8 weeks post conception, the majority of human fetuses move their right arms more than their left arms, but because nerve fibre tracts are still descending from the forebrain at this stage, spinal-muscular asymmetries are likely to play an important developmental role. Methods We used RNA sequencing to measure gene expression levels in the left and right spinal cords, and left and right hindbrains, of 18 post-mortem human embryos aged 4-8 weeks post conception. Genes showing embryonic lateralization were tested for an enrichment of signals in genome-wide association data for schizophrenia. Results The left side of the embryonic spinal cord was found to mature faster than the right side. Both sides transitioned from transcriptional profiles associated with cell division and proliferation at earlier stages, to neuronal differentiation and function at later stages, but the two sides were not in synchrony (p = 2.2 E-161). The hindbrain showed a left-right mirrored pattern compared to the spinal cord, consistent with the well-known crossing over of function between these two structures. Genes that showed lateralization in the embryonic spinal cord were enriched for association signals with schizophrenia (p = 4.3 E-05). Conclusions These are the earliest-stage left-right differences of human neural development ever reported. Disruption of the lateralised developmental programme may play a role in the genetic susceptibility to schizophrenia.

    Supplementary material

    mmc1.pdf
  • Ocklenburg, S., Schmitz, J., Moinfar, Z., Moser, D., Klose, R., Lor, S., Kunz, G., Tegenthoff, M., Faustmann, P., Francks, C., Epplen, J. T., Kumsta, R., & Güntürkün, O. (2017). Epigenetic regulation of lateralized fetal spinal gene expression underlies hemispheric asymmetries. eLife, 6: e22784. doi:10.7554/eLife.22784.001.

    Abstract

    Lateralization is a fundamental principle of nervous system organization but its molecular determinants are mostly unknown. In humans, asymmetric gene expression in the fetal cortex has been suggested as the molecular basis of handedness. However, human fetuses already show considerable asymmetries in arm movements before the motor cortex is functionally linked to the spinal cord, making it more likely that spinal gene expression asymmetries form the molecular basis of handedness. We analyzed genome-wide mRNA expression and DNA methylation in cervical and anterior thoracal spinal cord segments of five human fetuses and show development-dependent gene expression asymmetries. These gene expression asymmetries were epigenetically regulated by miRNA expression asymmetries in the TGF-β signaling pathway and lateralized methylation of CpG islands. Our findings suggest that molecular mechanisms for epigenetic regulation within the spinal cord constitute the starting point for handedness, implying a fundamental shift in our understanding of the ontogenesis of hemispheric asymmetries in humans
  • Thompson, P. M., Andreassen, O. A., Arias-Vasquez, A., Bearden, C. E., Boedhoe, P. S., Brouwer, R. M., Buckner, R. L., Buitelaar, J. K., Bulaeva, K. B., Cannon, D. M., Cohen, R. A., Conrod, P. J., Dale, A. M., Deary, I. J., Dennis, E. L., De Reus, M. A., Desrivieres, S., Dima, D., Donohoe, G., Fisher, S. E. and 51 moreThompson, P. M., Andreassen, O. A., Arias-Vasquez, A., Bearden, C. E., Boedhoe, P. S., Brouwer, R. M., Buckner, R. L., Buitelaar, J. K., Bulaeva, K. B., Cannon, D. M., Cohen, R. A., Conrod, P. J., Dale, A. M., Deary, I. J., Dennis, E. L., De Reus, M. A., Desrivieres, S., Dima, D., Donohoe, G., Fisher, S. E., Fouche, J.-P., Francks, C., Frangou, S., Franke, B., Ganjgahi, H., Garavan, H., Glahn, D. C., Grabe, H. J., Guadalupe, T., Gutman, B. A., Hashimoto, R., Hibar, D. P., Holland, D., Hoogman, M., Pol, H. E. H., Hosten, N., Jahanshad, N., Kelly, S., Kochunov, P., Kremen, W. S., Lee, P. H., Mackey, S., Martin, N. G., Mazoyer, B., McDonald, C., Medland, S. E., Morey, R. A., Nichols, T. E., Paus, T., Pausova, Z., Schmaal, L., Schumann, G., Shen, L., Sisodiya, S. M., Smit, D. J., Smoller, J. W., Stein, D. J., Stein, J. L., Toro, R., Turner, J. A., Van den Heuvel, M., Van den Heuvel, O. A., Van Erp, T. G., Van Rooij, D., Veltman, D. J., Walter, H., Wang, Y., Wardlaw, J. M., Whelan, C. D., Wright, M. J., & Ye, J. (2017). ENIGMA and the Individual: Predicting Factors that Affect the Brain in 35 Countries Worldwide. NeuroImage, 145, 389-408. doi:10.1016/j.neuroimage.2015.11.057.
  • Adams, H. H. H., Hibar, D. P., Chouraki, V., Stein, J. L., Nyquist, P., Renteria, M. E., Trompet, S., Arias-Vasquez, A., Seshadri, S., Desrivières, S., Beecham, A. H., Jahanshad, N., Wittfeld, K., Van der Lee, S. J., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K. A., Aribisala, B. S. and 322 moreAdams, H. H. H., Hibar, D. P., Chouraki, V., Stein, J. L., Nyquist, P., Renteria, M. E., Trompet, S., Arias-Vasquez, A., Seshadri, S., Desrivières, S., Beecham, A. H., Jahanshad, N., Wittfeld, K., Van der Lee, S. J., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K. A., Aribisala, B. S., Armstrong, N. J., Athanasiu, L., Axelsson, T., Beiser, A., Bernard, M., Bis, J. C., Blanken, L. M. E., Blanton, S. H., Bohlken, M. M., Boks, M. P., Bralten, J., Brickman, A. M., Carmichael, O., Chakravarty, M. M., Chauhan, G., Chen, Q., Ching, C. R. K., Cuellar-Partida, G., Den Braber, A., Doan, N. T., Ehrlich, S., Filippi, I., Ge, T., Giddaluru, S., Goldman, A. L., Gottesman, R. F., Greven, C. U., Grimm, O., Griswold, M. E., Guadalupe, T., Hass, J., Haukvik, U. K., Hilal, S., Hofer, E., Höhn, D., Holmes, A. J., Hoogman, M., Janowitz, D., Jia, T., Karbalai, N., Kasperaviciute, D., Kim, S., Klein, M., Krämer, B., Lee–, P. H., Liao, J., Liewald, D. C. M., Lopez, L. M., Luciano, M., Macare, C., Marquand, A., Matarin, M., Mather, K. A., Mattheisen, M., Mazoyer, B., McKay, D. R., McWhirter, R., Milaneschi, Y., Muetzel, R. L., Muñoz Maniega, S., Nho, K., Nugent, A. C., Olde Loohuis, L. M., Oosterlaan, J., Papmeyer, M., Pappa, I., Pirpamer, L., Pudas, S., Pütz, B., Rajan, K. B., Ramasamy, A., Richards, J. S., Risacher, S. L., Roiz-Santiañez, R., Rommelse, N., Rose, E. J., Royle, N. A., Rundek, T., Sämann, P. G., Satizabal, C. L., Schmaal, L., Schork, A. J., Shen, L., Shin, J., Shumskaya, E., Smith, A. V., Sprooten, E., Strike, L. T., Teumer, A., Thomson, R., Tordesillas-Gutierrez, D., Toro, R., Trabzuni, D., Vaidya, D., Van der Grond, J., Van der Meer, D., Van Donkelaar, M. M. J., Van Eijk, K. R., VanErp, T. G. M., Van Rooij, D., Walton, E., Westlye, L. T., Whelan, C. D., Windham, B. G., Winkler, A. M., Woldehawariat, G., Wolf, C., Wolfers, T., Xu, B., Yanek, L. R., Yang, J., Zijdenbos, A., Zwiers, M. P., Agartz, I., Aggarwal, N. T., Almasy, L., Ames, D., Amouyel, P., Andreassen, O. A., Arepalli, S., Assareh, A. A., Barral, S., Bastin, M. E., Becker, J. T., Becker, D. M., Bennett, D. A., Blangero, J., Van Bokhoven, H., Boomsma, D. I., Brodaty, H., Brouwer, R. M., Brunner, H. G., Buckner, R. L., Buitelaar, J. K., Bulayeva, K. B., Cahn, W., Calhoun, V. D., Cannon, D. M., Cavalleri, G. L., Chen, C., Cheng, C.-Y., Cichon, S., Cookson, M. R., Corvin, A., Crespo-Facorro, B., Curran, J. E., Czisch, M., Dale, A. M., Davies, G. E., De Geus, E. J. C., De Jager, P. L., De Zubicaray, G. I., Delanty, N., Depondt, C., DeStefano, A., Dillman, A., Djurovic, S., Donohoe, G., Drevets, W. C., Duggirala, R., Dyer, T. D., Erk, S., Espeseth, T., Evans, D. A., Fedko, I. O., Fernández, G., Ferrucci, L., Fisher, S. E., Fleischman, D. A., Ford, I., Foroud, T. M., Fox, P. T., Francks, C., Fukunaga, M., Gibbs, J. R., Glahn, D. C., Gollub, R. L., Göring, H. H. H., Grabe, H. J., Green, R. C., Gruber, O., Guelfi, S., Hansell, N. K., Hardy, J., Hartman, C. A., Hashimoto, R., Hegenscheid, K., Heinz, A., Le Hellard, S., Hernandez, D. G., Heslenfeld, D. J., Ho, B.-C., Hoekstra, P. J., Hoffmann, W., Hofman, A., Holsboer, F., Homuth, G., Hosten, N., Hottenga, J.-J., Hulshoff Pol, H. E., Ikeda, M., Ikram, M. K., Jack Jr, C. R., Jenkinson, M., Johnson, R., Jönsson, E. G., Jukema, J. W., Kahn, R. S., Kanai, R., Kloszewska, I., Knopman, D. S., Kochunov, P., Kwok, J. B., Launer, L. J., Lawrie, S. M., Lemaître, H., Liu, X., Longo, D. L., Longstreth Jr, W. T., Lopez, O. L., Lovestone, S., Martinez, O., Martinot, J.-L., Mattay, V. S., McDonald, C., McIntosh, A. M., McMahon, F. J., McMahon, K. L., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Mohnke, S., Montgomery, G. W., Morris, D. W., Mosley, T. H., Mühleisen, T. W., Müller-Myhsok, B., Nalls, M. A., Nauck, M., Nichols, T. E., Niessen, W. J., Nöthen, M. M., Nyberg, L., Ohi, K., Olvera, R. L., Ophoff, R. A., Pandolfo, M., Paus, T., Pausova, Z., Penninx, B. W. J. H., Pike, G. B., Potkin, S. G., Psaty, B. M., Reppermund, S., Rietschel, M., Roffman, J. L., Romanczuk-Seiferth, N., Rotter, J. I., Ryten, M., Sacco, R. L., Sachdev, P. S., Saykin, A. J., Schmidt, R., Schofield, P. R., Sigursson, S., Simmons, A., Singleton, A., Sisodiya, S. M., Smith, C., Smoller, J. W., Soininen, H., Srikanth, V., Steen, V. M., Stott, D. J., Sussmann, J. E., Thalamuthu, A., Tiemeier, H., Toga, A. W., Traynor, B., Troncoso, J., Turner, J. A., Tzourio, C., Uitterlinden, A. G., Valdés Hernández, M. C., Van der Brug, M., Van der Lugt, A., Van der Wee, N. J. A., Van Duijn, C. M., Van Haren, N. E. M., Van 't Ent, D., Van Tol, M.-J., Vardarajan, B. N., Veltman, D. J., Vernooij, M. W., Völzke, H., Walter, H., Wardlaw, J. M., Wassink, T. H., Weale, M. E., Weinberger, D. R., Weiner, M. W., Wen, W., Westman, E., White, T., Wong, T. Y., Wright, C. B., Zielke, R. H., Zonderman, A. B., the Alzheimer's Disease Neuroimaging Initiative, EPIGEN, IMAGEN, SYS, Deary, I. J., DeCarli, C., Schmidt, H., Martin, N. G., De Craen, A. J. M., Wright, M. J., Gudnason, V., Schumann, G., Fornage, M., Franke, B., Debette, S., Medland, S. E., Ikram, M. A., & Thompson, P. M. (2016). Novel genetic loci underlying human intracranial volume identified through genome-wide association. Nature Neuroscience, 19, 1569-1582. doi:10.1038/nn.4398.

    Abstract

    Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (genetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson’s disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth.
  • Becker, M., Guadalupe, T., Franke, B., Hibar, D. P., Renteria, M. E., Stein, J. L., Thompson, P. M., Francks, C., Vernes, S. C., & Fisher, S. E. (2016). Early developmental gene enhancers affect subcortical volumes in the adult human brain. Human Brain Mapping, 37(5), 1788-1800. doi:10.1002/hbm.23136.

    Abstract

    Genome-wide association screens aim to identify common genetic variants contributing to the phenotypic variability of complex traits, such as human height or brain morphology. The identified genetic variants are mostly within noncoding genomic regions and the biology of the genotype–phenotype association typically remains unclear. In this article, we propose a complementary targeted strategy to reveal the genetic underpinnings of variability in subcortical brain volumes, by specifically selecting genomic loci that are experimentally validated forebrain enhancers, active in early embryonic development. We hypothesized that genetic variation within these enhancers may affect the development and ultimately the structure of subcortical brain regions in adults. We tested whether variants in forebrain enhancer regions showed an overall enrichment of association with volumetric variation in subcortical structures of >13,000 healthy adults. We observed significant enrichment of genomic loci that affect the volume of the hippocampus within forebrain enhancers (empirical P = 0.0015), a finding which robustly passed the adjusted threshold for testing of multiple brain phenotypes (cutoff of P < 0.0083 at an alpha of 0.05). In analyses of individual single nucleotide polymorphisms (SNPs), we identified an association upstream of the ID2 gene with rs7588305 and variation in hippocampal volume. This SNP-based association survived multiple-testing correction for the number of SNPs analyzed but not for the number of subcortical structures. Targeting known regulatory regions offers a way to understand the underlying biology that connects genotypes to phenotypes, particularly in the context of neuroimaging genetics. This biology-driven approach generates testable hypotheses regarding the functional biology of identified associations.
  • Carrion Castillo, A., van Bergen, E., Vino, A., van Zuijen, T., de Jong, P. F., Francks, C., & Fisher, S. E. (2016). Evaluation of results from genome-wide studies of language and reading in a novel independent dataset. Genes, Brain and Behavior, 15(6), 531-541. doi:10.1111/gbb.12299.

    Abstract

    Recent genome wide association scans (GWAS) for reading and language abilities have pin-pointed promising new candidate loci. However, the potential contributions of these loci remain to be validated. In the present study, we tested 17 of the most significantly associated single nucleotide polymorphisms (SNPs) from these GWAS studies (p < 10−6 in the original studies) in a new independent population dataset from the Netherlands: known as FIOLA (Familial Influences On Literacy Abilities). This dataset comprised 483 children from 307 nuclear families, plus 505 adults (including parents of participating children), and provided adequate statistical power to detect the effects that were previously reported. The following measures of reading and language performance were collected: word reading fluency, nonword reading fluency, phonological awareness, and rapid automatized naming. Two SNPs (rs12636438, rs7187223) were associated with performance in multivariate and univariate testing, but these did not remain significant after correction for multiple testing. Another SNP (rs482700) was only nominally associated in the multivariate test. For the rest of the SNPs we did not find supportive evidence of association. The findings may reflect differences between our study and the previous investigations in respects such as the language of testing, the exact tests used, and the recruitment criteria. Alternatively, most of the prior reported associations may have been false positives. A larger scale GWAS meta-analysis than those previously performed will likely be required to obtain robust insights into the genomic architecture underlying reading and language.
  • Franke, B., Stein, J. L., Ripke, S., Anttila, V., Hibar, D. P., Van Hulzen, K. J. E., Arias-Vasquez, A., Smoller, J. W., Nichols, T. E., Neale, M. C., McIntosh, A. M., Lee, P., McMahon, F. J., Meyer-Lindenberg, A., Mattheisen, M., Andreassen, O. A., Gruber, O., Sachdev, P. S., Roiz-Santiañez, R., Saykin, A. J. and 17 moreFranke, B., Stein, J. L., Ripke, S., Anttila, V., Hibar, D. P., Van Hulzen, K. J. E., Arias-Vasquez, A., Smoller, J. W., Nichols, T. E., Neale, M. C., McIntosh, A. M., Lee, P., McMahon, F. J., Meyer-Lindenberg, A., Mattheisen, M., Andreassen, O. A., Gruber, O., Sachdev, P. S., Roiz-Santiañez, R., Saykin, A. J., Ehrlich, S., Mather, K. A., Turner, J. A., Schwarz, E., Thalamuthu, A., Yao, Y., Ho, Y. Y. W., Martin, N. G., Wright, M. J., Guadalupe, T., Fisher, S. E., Francks, C., Schizophrenia Working Group of the Psychiatric Genomics Consortium, ENIGMA Consortium, O’Donovan, M. C., Thompson, P. M., Neale, B. M., Medland, S. E., & Sullivan, P. F. (2016). Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept. Nature Neuroscience, 19, 420-431. doi:10.1038/nn.4228.

    Abstract

    Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders

    Supplementary material

    Franke_etal_2016_supp1.pdf
  • Gialluisi, A., Visconti, A., Wilcutt, E. G., Smith, S., Pennington, B., Falchi, M., DeFries, J., Olson, R., Francks, C., & Fisher, S. E. (2016). Investigating the effects of copy number variants on reading and language performance. Journal of Neurodevelopmental Disorders, 8: 17. doi:10.1186/s11689-016-9147-8.

    Abstract

    Background Reading and language skills have overlapping genetic bases, most of which are still unknown. Part of the missing heritability may be caused by copy number variants (CNVs). Methods In a dataset of children recruited for a history of reading disability (RD, also known as dyslexia) or attention deficit hyperactivity disorder (ADHD) and their siblings, we investigated the effects of CNVs on reading and language performance. First, we called CNVs with PennCNV using signal intensity data from Illumina OmniExpress arrays (~723,000 probes). Then, we computed the correlation between measures of CNV genomic burden and the first principal component (PC) score derived from several continuous reading and language traits, both before and after adjustment for performance IQ. Finally, we screened the genome, probe-by-probe, for association with the PC scores, through two complementary analyses: we tested a binary CNV state assigned for the location of each probe (i.e., CNV+ or CNV−), and we analyzed continuous probe intensity data using FamCNV. Results No significant correlation was found between measures of CNV burden and PC scores, and no genome-wide significant associations were detected in probe-by-probe screening. Nominally significant associations were detected (p~10−2–10−3) within CNTN4 (contactin 4) and CTNNA3 (catenin alpha 3). These genes encode cell adhesion molecules with a likely role in neuronal development, and they have been previously implicated in autism and other neurodevelopmental disorders. A further, targeted assessment of candidate CNV regions revealed associations with the PC score (p~0.026–0.045) within CHRNA7 (cholinergic nicotinic receptor alpha 7), which encodes a ligand-gated ion channel and has also been implicated in neurodevelopmental conditions and language impairment. FamCNV analysis detected a region of association (p~10−2–10−4) within a frequent deletion ~6 kb downstream of ZNF737 (zinc finger protein 737, uncharacterized protein), which was also observed in the association analysis using CNV calls. Conclusions These data suggest that CNVs do not underlie a substantial proportion of variance in reading and language skills. Analysis of additional, larger datasets is warranted to further assess the potential effects that we found and to increase the power to detect CNV effects on reading and language.
  • Kavaklioglu, T., Ajmal, M., Hameed, A., & Francks, C. (2016). Whole exome sequencing for handedness in a large and highly consanguineous family. Neuropsychologia, 93, part B, 342-349. doi:10.1016/j.neuropsychologia.2015.11.010.

    Abstract

    Pinpointing genes involved in non-right-handedness has the potential to clarify developmental contributions to human brain lateralization. Major-gene models have been considered for human handedness which allow for phenocopy and reduced penetrance, i.e. an imperfect correspondence between genotype and phenotype. However, a recent genome-wide association scan did not detect any common polymorphisms with substantial genetic effects. Previous linkage studies in families have also not yielded significant findings. Genetic heterogeneity and/or polygenicity are therefore indicated, but it remains possible that relatively rare, or even unique, major-genetic effects may be detectable in certain extended families with many non-right-handed members. Here we applied whole exome sequencing to 17 members from a single, large consanguineous family from Pakistan. Multipoint linkage analysis across all autosomes did not yield clear candidate genomic regions for involvement in the trait and single-point analysis of exomic variation did not yield clear candidate mutations/genes. Any genetic contribution to handedness in this unusual family is therefore likely to have a complex etiology, as at the population level.
  • Brucato, N., Guadalupe, T., Franke, B., Fisher, S. E., & Francks, C. (2015). A schizophrenia-associated HLA locus affects thalamus volume and asymmetry. Brain, Behavior, and Immunity, 46, 311-318. doi:10.1016/j.bbi.2015.02.021.

    Abstract

    Genes of the Major Histocompatibility Complex (MHC) have recently been shown to have neuronal functions in the thalamus and hippocampus. Common genetic variants in the Human Leukocyte Antigens (HLA) region, human homologue of the MHC locus, are associated with small effects on susceptibility to schizophrenia, while volumetric changes of the thalamus and hippocampus have also been linked to schizophrenia. We therefore investigated whether common variants of the HLA would affect volumetric variation of the thalamus and hippocampus. We analyzed thalamus and hippocampus volumes, as measured using structural magnetic resonance imaging, in 1.265 healthy participants. These participants had also been genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. We imputed genotypes for single nucleotide polymorphisms at high density across the HLA locus, as well as HLA allotypes and HLA amino acids, by use of a reference population dataset that was specifically targeted to the HLA region. We detected a significant association of the SNP rs17194174 with thalamus volume (nominal P=0.0000017, corrected P=0.0039), as well as additional SNPs within the same region of linkage disequilibrium. This effect was largely lateralized to the left thalamus and is localized within a genomic region previously associated with schizophrenia. The associated SNPs are also clustered within a potential regulatory element, and a region of linkage disequilibrium that spans genes expressed in the thalamus, including HLA-A. Our data indicate that genetic variation within the HLA region influences the volume and asymmetry of the human thalamus. The molecular mechanisms underlying this association may relate to HLA influences on susceptibility to schizophrenia
  • Ceroni, F., Simpson, N. H., Francks, C., Baird, G., Conti-Ramsden, G., Clark, A., Bolton, P. F., Hennessy, E. R., Donnelly, P., Bentley, D. R., Martin, H., IMGSAC, SLI Consortium, WGS500 Consortium, Parr, J., Pagnamenta, A. T., Maestrini, E., Bacchelli, E., Fisher, S. E., & Newbury, D. F. (2015). Reply to Pembrey et al: ‘ZNF277 microdeletions, specific language impairment and the meiotic mismatch methylation (3M) hypothesis’. European Journal of Human Genetics, 23, 1113-1115. doi:10.1038/ejhg.2014.275.
  • Francks, C. (2015). Exploring human brain lateralization with molecular genetics and genomics. Annals of the New York Academy of Sciences, 1359, 1-13. doi:10.1111/nyas.12770.

    Abstract

    Lateralizations of brain structure and motor behavior have been observed in humans as early as the first trimester of gestation, and are likely to arise from asymmetrical genetic–developmental programs, as in other animals. Studies of gene expression levels in postmortem tissue samples, comparing the left and right sides of the human cerebral cortex, have generally not revealed striking transcriptional differences between the hemispheres. This is likely due to lateralization of gene expression being subtle and quantitative. However, a recent re-analysis and meta-analysis of gene expression data from the adult superior temporal and auditory cortex found lateralization of transcription of genes involved in synaptic transmission and neuronal electrophysiology. Meanwhile, human subcortical mid- and hindbrain structures have not been well studied in relation to lateralization of gene activity, despite being potentially important developmental origins of asymmetry. Genetic polymorphisms with small effects on adult brain and behavioral asymmetries are beginning to be identified through studies of large datasets, but the core genetic mechanisms of lateralized human brain development remain unknown. Identifying subtly lateralized genetic networks in the brain will lead to a new understanding of how neuronal circuits on the left and right are differently fine-tuned to preferentially support particular cognitive and behavioral functions.
  • Guadalupe, T., Zwiers, M. P., Wittfeld, K., Teumer, A., Vasquez, A. A., Hoogman, M., Hagoort, P., Fernandez, G., Buitelaar, J., van Bokhoven, H., Hegenscheid, K., Völzke, H., Franke, B., Fisher, S. E., Grabe, H. J., & Francks, C. (2015). Asymmetry within and around the human planum temporale is sexually dimorphic and influenced by genes involved in steroid hormone receptor activity. Cortex, 62, 41-55. doi:10.1016/j.cortex.2014.07.015.

    Abstract

    The genetic determinants of cerebral asymmetries are unknown. Sex differences in asymmetry of the planum temporale, that overlaps Wernicke’s classical language area, have been inconsistently reported. Meta-analysis of previous studies has suggested that publication bias established this sex difference in the literature. Using probabilistic definitions of cortical regions we screened over the cerebral cortex for sexual dimorphisms of asymmetry in 2337 healthy subjects, and found the planum temporale to show the strongest sex-linked asymmetry of all regions, which was supported by two further datasets, and also by analysis with the Freesurfer package that performs automated parcellation of cerebral cortical regions. We performed a genome-wide association scan meta-analysis of planum temporale asymmetry in a pooled sample of 3095 subjects, followed by a candidate-driven approach which measured a significant enrichment of association in genes of the ´steroid hormone receptor activity´ and 'steroid metabolic process' pathways. Variants in the genes and pathways identified may affect the role of the planum temporale in language cognition.
  • Hibar, D. P., Stein, J. L., Renteria, M. E., Arias-Vasquez, A., Desrivières, S., Jahanshad, N., Toro, R., Wittfeld, K., Abramovic, L., Andersson, M., Aribisala, B. S., Armstrong, N. J., Bernard, M., Bohlken, M. M., Boks, M. P., Bralten, J., Brown, A. A., Chakravarty, M. M., Chen, Q., Ching, C. R. K. and 267 moreHibar, D. P., Stein, J. L., Renteria, M. E., Arias-Vasquez, A., Desrivières, S., Jahanshad, N., Toro, R., Wittfeld, K., Abramovic, L., Andersson, M., Aribisala, B. S., Armstrong, N. J., Bernard, M., Bohlken, M. M., Boks, M. P., Bralten, J., Brown, A. A., Chakravarty, M. M., Chen, Q., Ching, C. R. K., Cuellar-Partida, G., den Braber, A., Giddaluru, S., Goldman, A. L., Grimm, O., Guadalupe, T., Hass, J., Woldehawariat, G., Holmes, A. J., Hoogman, M., Janowitz, D., Jia, T., Kim, S., Klein, M., Kraemer, B., Lee, P. H., Olde Loohuis, L. M., Luciano, M., Macare, C., Mather, K. A., Mattheisen, M., Milaneschi, Y., Nho, K., Papmeyer, M., Ramasamy, A., Risacher, S. L., Roiz-Santiañez, R., Rose, E. J., Salami, A., Sämann, P. G., Schmaal, L., Schork, A. J., Shin, J., Strike, L. T., Teumer, A., Van Donkelaar, M. M. J., Van Eijk, K. R., Walters, R. K., Westlye, L. T., Whelan, C. D., Winkler, A. M., Zwiers, M. P., Alhusaini, S., Athanasiu, L., Ehrlich, S., Hakobjan, M. M. H., Hartberg, C. B., Haukvik, U. K., Heister, A. J. G. A. M., Hoehn, D., Kasperaviciute, D., Liewald, D. C. M., Lopez, L. M., Makkinje, R. R. R., Matarin, M., Naber, M. A. M., McKay, D. R., Needham, M., Nugent, A. C., Pütz, B., Royle, N. A., Shen, L., Sprooten, E., Trabzuni, D., Van der Marel, S. S. L., Van Hulzen, K. J. E., Walton, E., Wolf, C., Almasy, L., Ames, D., Arepalli, S., Assareh, A. A., Bastin, M. E., Brodaty, H., Bulayeva, K. B., Carless, M. A., Cichon, S., Corvin, A., Curran, J. E., Czisch, M., De Zubicaray, G. I., Dillman, A., Duggirala, R., Dyer, T. D., Erk, S., Fedko, I. O., Ferrucci, L., Foroud, T. M., Fox, P. T., Fukunaga, M., Gibbs, J. R., Göring, H. H. H., Green, R. C., Guelfi, S., Hansell, N. K., Hartman, C. A., Hegenscheid, K., Heinz, A., Hernandez, D. G., Heslenfeld, D. J., Hoekstra, P. J., Holsboer, F., Homuth, G., Hottenga, J.-J., Ikeda, M., Jack, C. R., Jenkinson, M., Johnson, R., Kanai, R., Keil, M., Kent, J. W., Kochunov, P., Kwok, J. B., Lawrie, S. M., Liu, X., Longo, D. L., McMahon, K. L., Meisenzahl, E., Melle, I., Mohnke, S., Montgomery, G. W., Mostert, J. C., Mühleisen, T. W., Nalls, M. A., Nichols, T. E., Nilsson, L. G., Nöthen, M. M., Ohi, K., Olvera, R. L., Perez-Iglesias, R., Pike, G. B., Potkin, S. G., Reinvang, I., Reppermund, S., Rietschel, M., Romanczuk-Seiferth, N., Rosen, G. D., Rujescu, D., Schnell, K., Schofield, P. R., Smith, C., Steen, V. M., Sussmann, J. E., Thalamuthu, A., Toga, A. W., Traynor, B. J., Troncoso, J., Turner, J. A., Valdes Hernández, M. C., van Ent, D. ’., Van der Brug, M., Van der Wee, N. J. A., Van Tol, M.-J., Veltman, D. J., Wassink, T. H., Westman, E., Zielke, R. H., Zonderman, A. B., Ashbrook, D. G., Hager, R., Lu, L., McMahon, F. J., Morris, D. W., Williams, R. W., Brunner, H. G., Buckner, R. L., Buitelaar, J. K., Cahn, W., Calhoun, V. D., Cavalleri, G. L., Crespo-Facorro, B., Dale, A. M., Davies, G. E., Delanty, N., Depondt, C., Djurovic, S., Drevets, W. C., Espeseth, T., Gollub, R. L., Ho, B.-C., Hoffmann, W., Hosten, N., Kahn, R. S., Le Hellard, S., Meyer-Lindenberg, A., Müller-Myhsok, B., Nauck, M., Nyberg, L., Pandolfo, M., Penninx, B. W. J. H., Roffman, J. L., Sisodiya, S. M., Smoller, J. W., Van Bokhoven, H., Van Haren, N. E. M., Völzke, H., Walter, H., Weiner, M. W., Wen, W., White, T., Agartz, I., Andreassen, O. A., Blangero, J., Boomsma, D. I., Brouwer, R. M., Cannon, D. M., Cookson, M. R., De Geus, E. J. C., Deary, I. J., Donohoe, G., Fernández, G., Fisher, S. E., Francks, C., Glahn, D. C., Grabe, H. J., Gruber, O., Hardy, J., Hashimoto, R., Hulshoff Pol, H. E., Jönsson, E. G., Kloszewska, I., Lovestone, S., Mattay, V. S., Mecocci, P., McDonald, C., McIntosh, A. M., Ophoff, R. A., Paus, T., Pausova, Z., Ryten, M., Sachdev, P. S., Saykin, A. J., Simmons, A., Singleton, A., Soininen, H., Wardlaw, J. M., Weale, M. E., Weinberger, D. R., Adams, H. H. H., Launer, L. J., Seiler, S., Schmidt, R., Chauhan, G., Satizabal, C. L., Becker, J. T., Yanek, L., van der Lee, S. J., Ebling, M., Fischl, B., Longstreth, W. T., Greve, D., Schmidt, H., Nyquist, P., Vinke, L. N., Van Duijn, C. M., Xue, L., Mazoyer, B., Bis, J. C., Gudnason, V., Seshadri, S., Ikram, M. A., The Alzheimer’s Disease Neuroimaging Initiative, The CHARGE Consortium, EPIGEN, IMAGEN, SYS, Martin, N. G., Wright, M. J., Schumann, G., Franke, B., Thompson, P. M., & Medland, S. E. (2015). Common genetic variants influence human subcortical brain structures. Nature, 520, 224-229. doi:10.1038/nature14101.

    Abstract

    The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10-33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction

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  • Karlebach, G., & Francks, C. (2015). Lateralization of gene expression in human language cortex. Cortex, 67, 30-36. doi:10.1016/j.cortex.2015.03.003.

    Abstract

    Lateralization is an important aspect of the functional brain architecture for language and other cognitive faculties. The molecular genetic basis of human brain lateralization is unknown, and recent studies have suggested that gene expression in the cerebral cortex is bilaterally symmetrical. Here we have re-analyzed two transcriptomic datasets derived from post mortem human cerebral cortex, with a specific focus on superior temporal and auditory language cortex in adults. We applied an empirical Bayes approach to model differential left-right expression, together with gene ontology analysis and meta-analysis. There was robust and reproducible lateralization of individual genes and gene ontology groups that are likely to fine-tune the electrophysiological and neurotransmission properties of cortical circuits, most notably synaptic transmission, nervous system development and glutamate receptor activity. Our findings anchor the cerebral biology of language to the molecular genetic level. Future research in model systems may determine how these molecular signatures of neurophysiological lateralization effect fine-tuning of cerebral cortical function, differently in the two hemispheres.
  • Villanueva, P., Nudel, R., Hoischen, A., Fernández, M. A., Simpson, N. H., Gilissen, C., Reader, R. H., Jara, L., Echeverry, M., Francks, C., Baird, G., Conti-Ramsden, G., O’Hare, A., Bolton, P., Hennessy, E. R., the SLI Consortium, Palomino, H., Carvajal-Carmona Veltman J.A., L., Veltman, J. A., Cazier, J.-B. and 3 moreVillanueva, P., Nudel, R., Hoischen, A., Fernández, M. A., Simpson, N. H., Gilissen, C., Reader, R. H., Jara, L., Echeverry, M., Francks, C., Baird, G., Conti-Ramsden, G., O’Hare, A., Bolton, P., Hennessy, E. R., the SLI Consortium, Palomino, H., Carvajal-Carmona Veltman J.A., L., Veltman, J. A., Cazier, J.-B., De Barbieri, Z., Fisher, S. E., & Newbury, D. (2015). Exome sequencing in an admixed isolated population indicates NFXL1 variants confer a risk for Specific Language Impairment. PLoS Genetics, 11(3): e1004925. doi:10.1371/journal.pgen.1004925.
  • Brucato, N., DeLisi, L. E., Fisher, S. E., & Francks, C. (2014). Hypomethylation of the paternally inherited LRRTM1 promoter linked to schizophrenia. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 165(7), 555-563. doi:10.1002/ajmg.b.32258.

    Abstract

    Epigenetic effects on psychiatric traits remain relatively under-studied, and it remains unclear what the sizes of individual epigenetic effects may be, or how they vary between different clinical populations. The gene LRRTM1 (chromosome 2p12) has previously been linked and associated with schizophrenia in a parent-of-origin manner in a set of affected siblings (LOD = 4.72), indirectly suggesting a disruption of paternal imprinting at this locus in these families. From the same set of siblings that originally showed strong linkage at this locus, we analyzed 99 individuals using 454-bisulfite sequencing, from whole blood DNA, to measure the level of DNA methylation in the promoter region of LRRTM1. We also assessed seven additional loci that would be informative to compare. Paternal identity-by-descent sharing at LRRTM1, within sibling pairs, was linked to their similarity of methylation at the gene's promoter. Reduced methylation at the promoter showed a significant association with schizophrenia. Sibling pairs concordant for schizophrenia showed more similar methylation levels at the LRRTM1 promoter than diagnostically discordant pairs. The alleles of common SNPs spanning the locus did not explain this epigenetic linkage, which can therefore be considered as largely independent of DNA sequence variation and would not be detected in standard genetic association analysis. Our data suggest that hypomethylation at the LRRTM1 promoter, particularly of the paternally inherited allele, was a risk factor for the development of schizophrenia in this set of siblings affected with familial schizophrenia, and that had previously showed linkage at this locus in an affected-sib-pair context.
  • Cai, D., Fonteijn, H. M., Guadalupe, T., Zwiers, M., Wittfeld, K., Teumer, A., Hoogman, M., Arias Vásquez, A., Yang, Y., Buitelaar, J., Fernández, G., Brunner, H. G., Van Bokhoven, H., Franke, B., Hegenscheid, K., Homuth, G., Fisher, S. E., Grabe, H. J., Francks, C., & Hagoort, P. (2014). A genome wide search for quantitative trait loci affecting the cortical surface area and thickness of Heschl's gyrus. Genes, Brain and Behavior, 13, 675-685. doi:10.1111/gbb.12157.

    Abstract

    Heschl's gyrus (HG) is a core region of the auditory cortex whose morphology is highly variable across individuals. This variability has been linked to sound perception ability in both speech and music domains. Previous studies show that variations in morphological features of HG, such as cortical surface area and thickness, are heritable. To identify genetic variants that affect HG morphology, we conducted a genome-wide association scan (GWAS) meta-analysis in 3054 healthy individuals using HG surface area and thickness as quantitative traits. None of the single nucleotide polymorphisms (SNPs) showed association P values that would survive correction for multiple testing over the genome. The most significant association was found between right HG area and SNP rs72932726 close to gene DCBLD2 (3q12.1; P=2.77x10(-7)). This SNP was also associated with other regions involved in speech processing. The SNP rs333332 within gene KALRN (3q21.2; P=2.27x10(-6)) and rs143000161 near gene COBLL1 (2q24.3; P=2.40x10(-6)) were associated with the area and thickness of left HG, respectively. Both genes are involved in the development of the nervous system. The SNP rs7062395 close to the X-linked deafness gene POU3F4 was associated with right HG thickness (Xq21.1; P=2.38x10(-6)). This is the first molecular genetic analysis of variability in HG morphology
  • Ceroni, F., Simpson, N. H., Francks, C., Baird, G., Conti-Ramsden, G., Clark, A., Bolton, P. F., Hennessy, E. R., Donnelly, P., Bentley, D. R., Martin, H., IMGSAC, SLI Consortium, WGS500 Consortium, Parr, J., Pagnamenta, A. T., Maestrini, E., Bacchelli, E., Fisher, S. E., & Newbury, D. F. (2014). Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment. European Journal of Human Genetics, 22, 1165-1171. doi:10.1038/ejhg.2014.4.

    Abstract

    Specific language impairment (SLI), an unexpected failure to develop appropriate language skills despite adequate non-verbal intelligence, is a heterogeneous multifactorial disorder with a complex genetic basis. We identified a homozygous microdeletion of 21,379 bp in the ZNF277 gene (NM_021994.2), encompassing exon 5, in an individual with severe receptive and expressive language impairment. The microdeletion was not found in the proband’s affected sister or her brother who had mild language impairment. However, it was inherited from both parents, each of whom carries a heterozygous microdeletion and has a history of language problems. The microdeletion falls within the AUTS1 locus, a region linked to autistic spectrum disorders (ASDs). Moreover, ZNF277 is adjacent to the DOCK4 and IMMP2L genes, which have been implicated in ASD. We screened for the presence of ZNF277 microdeletions in cohorts of children with SLI or ASD and panels of control subjects. ZNF277 microdeletions were at an increased allelic frequency in SLI probands (1.1%) compared with both ASD family members (0.3%) and independent controls (0.4%). We performed quantitative RT-PCR analyses of the expression of IMMP2L, DOCK4 and ZNF277 in individuals carrying either an IMMP2L_DOCK4 microdeletion or a ZNF277 microdeletion. Although ZNF277 microdeletions reduce the expression of ZNF277, they do not alter the levels of DOCK4 or IMMP2L transcripts. Conversely, IMMP2L_DOCK4 microdeletions do not affect the expression levels of ZNF277. We postulate that ZNF277 microdeletions may contribute to the risk of language impairments in a manner that is independent of the autism risk loci previously described in this region.
  • Gialluisi, A., Newbury, D. F., Wilcutt, E. G., Olson, R. K., DeFries, J. C., Brandler, W. M., Pennington, B. F., Smith, S. D., Scerri, T. S., Simpson, N. H., The SLI Consortium, Luciano, M., Evans, D. M., Bates, T. C., Stein, J. F., Talcott, J. B., Monaco, A. P., Paracchini, S., Francks, C., & Fisher, S. E. (2014). Genome-wide screening for DNA variants associated with reading and language traits. Genes, Brain and Behavior, 13, 686-701. doi:10.1111/gbb.12158.

    Abstract

    Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a Genome-wide Association Scan (GWAS) meta-analysis using three richly characterised datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading- and language-related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected p≈10−7 for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on-going international efforts to identify genes contributing to reading and language skills.
  • Guadalupe, T., Zwiers, M. P., Teumer, A., Wittfeld, K., Arias Vasquez, A., Hoogman, M., Hagoort, P., Fernández, G., Buitelaar, J., Hegenscheid, K., Völzke, H., Franke, B., Fisher, S. E., Grabe, H. J., & Francks, C. (2014). Measurement and genetics of human subcortical and hippocampal asymmetries in large datasets. Human Brain Mapping, 35(7), 3277-3289. doi:10.1002/hbm.22401.

    Abstract

    Functional and anatomical asymmetries are prevalent features of the human brain, linked to gender, handedness, and cognition. However, little is known about the neurodevelopmental processes involved. In zebrafish, asymmetries arise in the diencephalon before extending within the central nervous system. We aimed to identify genes involved in the development of subtle, left-right volumetric asymmetries of human subcortical structures using large datasets. We first tested the feasibility of measuring left-right volume differences in such large-scale samples, as assessed by two automated methods of subcortical segmentation (FSL|FIRST and FreeSurfer), using data from 235 subjects who had undergone MRI twice. We tested the agreement between the first and second scan, and the agreement between the segmentation methods, for measures of bilateral volumes of six subcortical structures and the hippocampus, and their volumetric asymmetries. We also tested whether there were biases introduced by left-right differences in the regional atlases used by the methods, by analyzing left-right flipped images. While many bilateral volumes were measured well (scan-rescan r = 0.6-0.8), most asymmetries, with the exception of the caudate nucleus, showed lower repeatabilites. We meta-analyzed genome-wide association scan results for caudate nucleus asymmetry in a combined sample of 3,028 adult subjects but did not detect associations at genome-wide significance (P < 5 × 10-8). There was no enrichment of genetic association in genes involved in left-right patterning of the viscera. Our results provide important information for researchers who are currently aiming to carry out large-scale genome-wide studies of subcortical and hippocampal volumes, and their asymmetries
  • Guadalupe, T., Willems, R. M., Zwiers, M., Arias Vasquez, A., Hoogman, M., Hagoort, P., Fernández, G., Buitelaar, J., Franke, B., Fisher, S. E., & Francks, C. (2014). Differences in cerebral cortical anatomy of left- and right-handers. Frontiers in Psychology, 5: 261. doi:10.3389/fpsyg.2014.00261.

    Abstract

    The left and right sides of the human brain are specialized for different kinds of information processing, and much of our cognition is lateralized to an extent towards one side or the other. Handedness is a reflection of nervous system lateralization. Roughly ten percent of people are mixed- or left-handed, and they show an elevated rate of reductions or reversals of some cerebral functional asymmetries compared to right-handers. Brain anatomical correlates of left-handedness have also been suggested. However, the relationships of left-handedness to brain structure and function remain far from clear. We carried out a comprehensive analysis of cortical surface area differences between 106 left-handed subjects and 1960 right-handed subjects, measured using an automated method of regional parcellation (FreeSurfer, Destrieux atlas). This is the largest study sample that has so far been used in relation to this issue. No individual cortical region showed an association with left-handedness that survived statistical correction for multiple testing, although there was a nominally significant association with the surface area of a previously implicated region: the left precentral sulcus. Identifying brain structural correlates of handedness may prove useful for genetic studies of cerebral asymmetries, as well as providing new avenues for the study of relations between handedness, cerebral lateralization and cognition.
  • Hoogman, M., Guadalupe, T., Zwiers, M. P., Klarenbeek, P., Francks, C., & Fisher, S. E. (2014). Assessing the effects of common variation in the FOXP2 gene on human brain structure. Frontiers in Human Neuroscience, 8: 473. doi:10.3389/fnhum.2014.00473.

    Abstract

    The FOXP2 transcription factor is one of the most well-known genes to have been implicated in developmental speech and language disorders. Rare mutations disrupting the function of this gene have been described in different families and cases. In a large three-generation family carrying a missense mutation, neuroimaging studies revealed significant effects on brain structure and function, most notably in the inferior frontal gyrus, caudate nucleus and cerebellum. After the identification of rare disruptive FOXP2 variants impacting on brain structure, several reports proposed that common variants at this locus may also have detectable effects on the brain, extending beyond disorder into normal phenotypic variation. These neuroimaging genetics studies used groups of between 14 and 96 participants. The current study assessed effects of common FOXP2 variants on neuroanatomy using voxel-based morphometry and volumetric techniques in a sample of >1300 people from the general population. In a first targeted stage we analyzed single nucleotide polymorphisms (SNPs) claimed to have effects in prior smaller studies (rs2253478, rs12533005, rs2396753, rs6980093, rs7784315, rs17137124, rs10230558, rs7782412, rs1456031), beginning with regions proposed in the relevant papers, then assessing impact across the entire brain. In the second gene-wide stage, we tested all common FOXP2 variation, focusing on volumetry of those regions most strongly implicated from analyses of rare disruptive mutations. Despite using a sample that is more than ten times that used for prior studies of common FOXP2 variation, we found no evidence for effects of SNPs on variability in neuroanatomy in the general population. Thus, the impact of this gene on brain structure may be largely limited to extreme cases of rare disruptive alleles. Alternatively, effects of common variants at this gene exist but are too subtle to be detected with standard volumetric techniques
  • Nudel, R., Simpson, N. H., Baird, G., O’Hare, A., Conti-Ramsden, G., Bolton, P. F., Hennessy, E. R., The SLli consortium, Ring, S. M., Smith, G. D., Francks, C., Paracchini, S., Monaco, A. P., Fisher, S. E., & Newbury, D. F. (2014). Genome-wide association analyses of child genotype effects and parent-of origin effects in specific language impairment. Genes, Brain and Behavior, 13, 418-429. doi:10.1111/gbb.12127.

    Abstract

    Specific language impairment (SLI) is a neurodevelopmental disorder that affects linguistic abilities when development is otherwise normal. We report the results of a genomewide association study of SLI which included parent-of-origin effects and child genotype effects and used 278 families of language-impaired children. The child genotype effects analysis did not identify significant associations. We found genome-wide significant paternal parent-of-origin effects on chromosome 14q12 (P=3.74×10-8) and suggestive maternal parent-of-origin-effects on chromosome 5p13 (P=1.16×10-7). A subsequent targeted association of six single-nucleotide-polymorphisms (SNPs) on chromosome 5 in 313 language-impaired individuals from the ALSPAC cohort replicated the maternal effects, albeit in the opposite direction (P=0.001); as fathers’ genotypes were not available in the ALSPAC study, the replication analysis did not include paternal parent-of-origin effects. The paternally-associated SNP on chromosome 14 yields a non-synonymous coding change within the NOP9 gene. This gene encodes an RNA-binding protein that has been reported to be significantly dysregulated in individuals with schizophrenia. The region of maternal association on chromosome 5 falls between the PTGER4 and DAB2 genes, in a region previously implicated in autism and ADHD. The top SNP in this association locus is a potential expression QTL of ARHGEF19 (also called WGEF) on chromosome 1. Members of this protein family have been implicated in intellectual disability. In sum, this study implicates parent-of-origin effects in language impairment, and adds an interesting new dimension to the emerging picture of shared genetic etiology across various neurodevelopmental disorders.
  • Thompson, P. M., Stein, J. L., Medland, S. E., Hibar, D. P., Vasquez, A. A., Renteria, M. E., Toro, R., Jahanshad, N., Schumann, G., Franke, B., Wright, M. J., Martin, N. G., Agartz, I., Alda, M., Alhusaini, S., Almasy, L., Almeida, J., Alpert, K., Andreasen, N. C., Andreassen, O. A. and 269 moreThompson, P. M., Stein, J. L., Medland, S. E., Hibar, D. P., Vasquez, A. A., Renteria, M. E., Toro, R., Jahanshad, N., Schumann, G., Franke, B., Wright, M. J., Martin, N. G., Agartz, I., Alda, M., Alhusaini, S., Almasy, L., Almeida, J., Alpert, K., Andreasen, N. C., Andreassen, O. A., Apostolova, L. G., Appel, K., Armstrong, N. J., Aribisala, B., Bastin, M. E., Bauer, M., Bearden, C. E., Bergmann, Ø., Binder, E. B., Blangero, J., Bockholt, H. J., Bøen, E., Bois, C., Boomsma, D. I., Booth, T., Bowman, I. J., Bralten, J., Brouwer, R. M., Brunner, H. G., Brohawn, D. G., Buckner, R. L., Buitelaar, J., Bulayeva, K., Bustillo, J. R., Calhoun, V. D., Cannon, D. M., Cantor, R. M., Carless, M. A., Caseras, X., Cavalleri, G. L., Chakravarty, M. M., Chang, K. D., Ching, C. R. K., Christoforou, A., Cichon, S., Clark, V. P., Conrod, P., Coppola, G., Crespo-Facorro, B., Curran, J. E., Czisch, M., Deary, I. J., de Geus, E. J. C., den Braber, A., Delvecchio, G., Depondt, C., de Haan, L., de Zubicaray, G. I., Dima, D., Dimitrova, R., Djurovic, S., Dong, H., Donohoe, G., Duggirala, R., Dyer, T. D., Ehrlich, S., Ekman, C. J., Elvsåshagen, T., Emsell, L., Erk, S., Espeseth, T., Fagerness, J., Fears, S., Fedko, I., Fernández, G., Fisher, S. E., Foroud, T., Fox, P. T., Francks, C., Frangou, S., Frey, E. M., Frodl, T., Frouin, V., Garavan, H., Giddaluru, S., Glahn, D. C., Godlewska, B., Goldstein, R. Z., Gollub, R. L., Grabe, H. J., Grimm, O., Gruber, O., Guadalupe, T., Gur, R. E., Gur, R. C., Göring, H. H. H., Hagenaars, S., Hajek, T., Hall, G. B., Hall, J., Hardy, J., Hartman, C. A., Hass, J., Hatton, S. N., Haukvik, U. K., Hegenscheid, K., Heinz, A., Hickie, I. B., Ho, B.-C., Hoehn, D., Hoekstra, P. J., Hollinshead, M., Holmes, A. J., Homuth, G., Hoogman, M., Hong, L. E., Hosten, N., Hottenga, J.-J., Pol, H. E. H., Hwang, K. S., Jr, C. R. J., Jenkinson, M., Johnston, C., Jönsson, E. G., Kahn, R. S., Kasperaviciute, D., Kelly, S., Kim, S., Kochunov, P., Koenders, L., Krämer, B., Kwok, J. B. J., Lagopoulos, J., Laje, G., Landen, M., Landman, B. A., Lauriello, J., Lawrie, S. M., Lee, P. H., Le Hellard, S., Lemaître, H., Leonardo, C. D., Li, C.-s., Liberg, B., Liewald, D. C., Liu, X., Lopez, L. M., Loth, E., Lourdusamy, A., Luciano, M., Macciardi, F., Machielsen, M. W. J., MacQueen, G. M., Malt, U. F., Mandl, R., Manoach, D. S., Martinot, J.-L., Matarin, M., Mather, K. A., Mattheisen, M., Mattingsdal, M., Meyer-Lindenberg, A., McDonald, C., McIntosh, A. M., McMahon, F. J., McMahon, K. L., Meisenzahl, E., Melle, I., Milaneschi, Y., Mohnke, S., Montgomery, G. W., Morris, D. W., Moses, E. K., Mueller, B. A., Maniega, S. M., Mühleisen, T. W., Müller-Myhsok, B., Mwangi, B., Nauck, M., Nho, K., Nichols, T. E., Nilsson, L.-G., Nugent, A. C., Nyberg, L., Olvera, R. L., Oosterlaan, J., Ophoff, R. A., Pandolfo, M., Papalampropoulou-Tsiridou, M., Papmeyer, M., Paus, T., Pausova, Z., Pearlson, G. D., Penninx, B. W., Peterson, C. P., Pfennig, A., Phillips, M., Pike, G. B., Poline, J.-B., Potkin, S. G., Pütz, B., Ramasamy, A., Rasmussen, J., Rietschel, M., Rijpkema, M., Risacher, S. L., Roffman, J. L., Roiz-Santiañez, R., Romanczuk-Seiferth, N., Rose, E. J., Royle, N. A., Rujescu, D., Ryten, M., Sachdev, P. S., Salami, A., Satterthwaite, T. D., Savitz, J., Saykin, A. J., Scanlon, C., Schmaal, L., Schnack, H. G., Schork, A. J., Schulz, S. C., Schür, R., Seidman, L., Shen, L., Shoemaker, J. M., Simmons, A., Sisodiya, S. M., Smith, C., Smoller, J. W., Soares, J. C., Sponheim, S. R., Sprooten, E., Starr, J. M., Steen, V. M., Strakowski, S., Strike, L., Sussmann, J., Sämann, P. G., Teumer, A., Toga, A. W., Tordesillas-Gutierrez, D., Trabzuni, D., Trost, S., Turner, J., Van den Heuvel, M., van der Wee, N. J., van Eijk, K., van Erp, T. G. M., van Haren, N. E. M., van Ent, D. ‘., van Tol, M.-J., Hernández, M. C. V., Veltman, D. J., Versace, A., Völzke, H., Walker, R., Walter, H., Wang, L., Wardlaw, J. M., Weale, M. E., Weiner, M. W., Wen, W., Westlye, L. T., Whalley, H. C., Whelan, C. D., White, T., Winkler, A. M., Wittfeld, K., Woldehawariat, G., Wolf, C., Zilles, D., Zwiers, M. P., Thalamuthu, A., Schofield, P. R., Freimer, N. B., Lawrence, N. S., & Drevets, W. (2014). The ENIGMA Consortium: Large-scale collaborative analyses of neuroimaging and genetic data. Brain Imaging and Behavior, 8(2), 153-182. doi:10.1007/s11682-013-9269-5.

    Abstract

    The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA’s first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way
  • Tosato, S., Zanoni, M., Bonetto, C., Tozzi, F., Francks, C., Ira, E., Tomassi, S., Bertani, M., Rujescu, D., Giegling, I., St Clair, D., Tansella, M., Ruggeri, M., & Muglia, P. (2014). No association between NRG1 and ErbB4 genes and psychopathological symptoms of Schizophrenia. Neuromolecular Medicine, 16, 742-751. doi:10.1007/s12017-014-8323-9.

    Abstract

    Neuregulin 1 (NRG1) and v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) have been extensively studied in schizophrenia susceptibility because of their pivotal role in key neurodevelopmental processes. One of the reasons for the inconsistencies in results could be the fact that the phenotype investigated has mostly the diagnosis of schizophrenia per se, which is widely heterogeneous, both clinically and biologically. In the present study we tested, in a large cohort of 461 schizophrenia patients recruited in Scotland, whether several SNPs in NRG1 and/or ErbB4 are associated with schizophrenia symptom dimensions as evaluated by the Positive and Negative Syndrome Scale (PANSS). We then followed up nominally significant results in a second cohort of 439 schizophrenia subjects recruited in Germany. Using linear regression, we observed two different groups of polymorphisms in NRG1 gene: one showing a nominal association with higher scores of the PANSS positive dimension and the other one with higher scores of the PANSS negative dimension. Regarding ErbB4, a small cluster located in the 5' end of the gene was detected, showing nominal association mainly with negative, general and total dimensions of the PANSS. These findings suggest that some regions of NRG1 and ErbB4 are functionally involved in biological processes that underlie some of the phenotypic manifestations of schizophrenia. Because of the lack of significant association after correction for multiple testing, our analyses should be considered as exploratory and hypothesis generating for future studies.
  • Willems, R. M., Van der Haegen, L., Fisher, S. E., & Francks, C. (2014). On the other hand: Including left-handers in cognitive neuroscience and neurogenetics. Nature Reviews Neuroscience, 15, 193-201. doi:10.1038/nrn3679.

    Abstract

    Left-handers are often excluded from study cohorts in neuroscience and neurogenetics in order to reduce variance in the data. However, recent investigations have shown that the inclusion or targeted recruitment of left-handers can be informative in studies on a range of topics, such as cerebral lateralization and the genetic underpinning of asymmetrical brain development. Left-handed individuals represent a substantial portion of the human population and therefore left-handedness falls within the normal range of human diversity; thus, it is important to account for this variation in our understanding of brain functioning. We call for neuroscientists and neurogeneticists to recognize the potential of studying this often-discarded group of research subjects.
  • Willems, R. M., & Francks, C. (2014). Your left-handed brain. Frontiers for Young Minds, 2: 13. doi:10.3389/frym.2014.00013.

    Abstract

    While most people prefer to use their right hand to brush their teeth, throw a ball, or hold a tennis racket, left-handers prefer to use their left hand. This is the case for around 10 per cent of all people. There was a time (not so long ago) when left-handers were stigmatized in Western (and other) communities: it was considered a bad sign if you were left-handed, and left-handed children were often forced to write with their right hand. This is nonsensical: there is nothing wrong with being left-handed, and trying to write with the non-preferred hand is frustrating for almost everybody. As a matter of fact, science can learn from left-handers, and in this paper, we discuss how this may be the case. We review why some people are left-handed and others are not, how left-handers' brains differ from right-handers’, and why scientists study left-handedness in the first place
  • Gialluisi, A., Dediu, D., Francks, C., & Fisher, S. E. (2013). Persistence and transmission of recessive deafness and sign language: New insights from village sign languages. European Journal of Human Genetics, 21, 894-896. doi:10.1038/ejhg.2012.292.

    Abstract

    First paragraph: The study of the transmission of sign languages can give novel insights into the transmission of spoken languages1 and, more generally, into gene–culture coevolution. Over the years, several papers related to the persistence of sign language have been reported.2–6 All of these studies have emphasized the role of assortative (non-random) mating by deafness state (ie, a tendency for deaf individuals to partner together) for increasing the frequency of recessive deafness, and hence for the persistence of sign language in a population.
  • Stephens, S., Hartz, S., Hoft, N., Saccone, N., Corley, R., Hewitt, J., Hopfer, C., Breslau, N., Coon, H., Chen, X., Ducci, F., Dueker, N., Franceschini, N., Frank, J., Han, Y., Hansel, N., Jiang, C., Korhonen, T., Lind, P., Liu, J. and 105 moreStephens, S., Hartz, S., Hoft, N., Saccone, N., Corley, R., Hewitt, J., Hopfer, C., Breslau, N., Coon, H., Chen, X., Ducci, F., Dueker, N., Franceschini, N., Frank, J., Han, Y., Hansel, N., Jiang, C., Korhonen, T., Lind, P., Liu, J., Michel, M., Lyytikäinen, L.-P., Shaffer, J., Short, S., Sun, J., Teumer, A., Thompson, J., Vogelzangs, N., Vink, J., Wenzlaff, A., Wheeler, W., Yang, B.-Z., Aggen, S., Balmforth, A., Baumesiter, S., Beaty, T., Benjamin, D., Bergen, A., Broms, U., Cesarini, D., Chatterjee, N., Chen, J., Cheng, Y.-C., Cichon, S., Couper, D., Cucca, F., Dick, D., Foround, T., Furberg, H., Giegling, I., Gillespie, N., Gu, F.,.Hall, A., Hällfors, J., Han, S., Hartmann, A., Heikkilä, K., Hickie, I., Hottenga, J., Jousilahti, P., Kaakinen, M., Kähönen, M., Koellinger, P., Kittner, S., Konte, B., Landi, M.-T., Laatikainen, T., Leppert, M., Levy, S., Mathias, R., McNeil, D., Medlund, S., Montgomery, G., Murray, T., Nauck, M., North, K., Paré, P., Pergadia, M., Ruczinski, I., Salomaa, V., Viikari, J., Willemsen, G., Barnes, K., Boerwinkle, E., Boomsma, D., Caporaso, N., Edenberg, H., Francks, C., Gelernter, J., Grabe, H., Hops, H., Jarvelin, M.-R., Johannesson, M., Kendler, K., Lehtimäki, T., Magnusson, P., Marazita, M., Marchini, J., Mitchell, B., Nöthen, M., Penninx, B., Raitakari, O., Rietschel, M., Rujescu, D., Samani, N., Schwartz, A., Shete, S., Spitz, M., Swan, G., Völzke, H., Veijola, J., Wei, Q., Amos, C., Canon, D., Grucza, R., Hatsukami, D., Heath, A., Johnson, E., Kaprio, J., Madden, P., Martin, N., Stevens, V., Weiss, R., Kraft, P., Bierut, L., & Ehringer, M. (2013). Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster are Associated with Onset of Regular Smoking. Genetic Epidemiology, 37, 846-859. doi:10.1002/gepi.21760.

    Abstract

    Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype

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  • Hartz, S. M., Short, S. E., Saccone, N. L., Culverhouse, R., Chen, L., Schwantes-An, T.-H., Coon, H., Han, Y., Stephens, S. H., Sun, J., Chen, X., Ducci, F., Dueker, N., Franceschini, N., Frank, J., Geller, F., Gubjartsson, D., Hansel, N. N., Jiang, C., Keskitalo-Vuokko, K. and 132 moreHartz, S. M., Short, S. E., Saccone, N. L., Culverhouse, R., Chen, L., Schwantes-An, T.-H., Coon, H., Han, Y., Stephens, S. H., Sun, J., Chen, X., Ducci, F., Dueker, N., Franceschini, N., Frank, J., Geller, F., Gubjartsson, D., Hansel, N. N., Jiang, C., Keskitalo-Vuokko, K., Liu, Z., Lyytikainen, L.-P., Michel, M., Rawal, R., Rosenberger, A., Scheet, P., Shaffer, J. R., Teumer, A., Thompson, J. R., Vink, J. M., Vogelzangs, N., Wenzlaff, A. S., Wheeler, W., Xiao, X., Yang, B.-Z., Aggen, S. H., Balmforth, A. J., Baumeister, S. E., Beaty, T., Bennett, S., Bergen, A. W., Boyd, H. A., Broms, U., Campbell, H., Chatterjee, N., Chen, J., Cheng, Y.-C., Cichon, S., Couper, D., Cucca, F., Dick, D. M., Foroud, T., Furberg, H., Giegling, I., Gu, F., Hall, A. S., Hallfors, J., Han, S., Hartmann, A. M., Hayward, C., Heikkila, K., Hewitt, J. K., Hottenga, J. J., Jensen, M. K., Jousilahti, P., Kaakinen, M., Kittner, S. J., Konte, B., Korhonen, T., Landi, M.-T., Laatikainen, T., Leppert, M., Levy, S. M., Mathias, R. A., McNeil, D. W., Medland, S. E., Montgomery, G. W., Muley, T., Murray, T., Nauck, M., North, K., Pergadia, M., Polasek, O., Ramos, E. M., Ripatti, S., Risch, A., Ruczinski, I., Rudan, I., Salomaa, V., Schlessinger, D., Styrkarsdottir, U., Terracciano, A., Uda, M., Willemsen, G., Wu, X., Abecasis, G., Barnes, K., Bickeboller, H., Boerwinkle, E., Boomsma, D. I., Caporaso, N., Duan, J., Edenberg, H. J., Francks, C., Gejman, P. V., Gelernter, J., Grabe, H. J., Hops, H., Jarvelin, M.-R., Viikari, J., Kahonen, M., Kendler, K. S., Lehtimaki, T., Levinson, D. F., Marazita, M. L., Marchini, J., Melbye, M., Mitchell, B., Murray, J. C., Nothen, M. M., Penninx, B. W., Raitakari, O., Rietschel, M., Rujescu, D., Samani, N. J., Sanders, A. R., Schwartz, A. G., Shete, S., Shi, J., Spitz, M., Stefansson, K., Swan, G. E., Thorgeirsson, T., Volzke, H., Wei, Q., Wichmann, H.-E., Amos, C. I., Breslau, N., Cannon, D. S., Ehringer, M., Grucza, R., Hatsukami, D., Heath, A., Johnson, E. O., Kaprio, J., Madden, P., Martin, N. G., Stevens, V. L., Stitzel, J. A., Weiss, R. B., Kraft, P., & Bierut, L. J. (2012). Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers. Archives of General Psychiatry, 69, 854-860. doi:10.1001/archgenpsychiatry.2012.124.

    Abstract

    CONTEXT Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. OBJECTIVE To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. DATA SOURCES Primary data. STUDY SELECTION Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. DATA EXTRACTION Uniform statistical analysis scripts were run locally. Starting with 94 050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33 348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. DATA SYNTHESIS Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13 843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19 505) (P = .01). CONCLUSION These results highlight an increased genetic vulnerability to smoking in early-onset smokers.

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  • Artigas, M. S., Loth, D. W., Wain, L. V., Gharib, S. A., Obeidat, M., Tang, W., Zhai, G., Zhao, J. H., Smith, A. V., Huffman, J. E., Albrecht, E., Jackson, C. M., Evans, D. M., Cadby, G., Fornage, M., Manichaikul, A., Lopez, L. M., Johnson, T., Aldrich, M. C., Aspelund, T. and 149 moreArtigas, M. S., Loth, D. W., Wain, L. V., Gharib, S. A., Obeidat, M., Tang, W., Zhai, G., Zhao, J. H., Smith, A. V., Huffman, J. E., Albrecht, E., Jackson, C. M., Evans, D. M., Cadby, G., Fornage, M., Manichaikul, A., Lopez, L. M., Johnson, T., Aldrich, M. C., Aspelund, T., Barroso, I., Campbell, H., Cassano, P. A., Couper, D. J., Eiriksdottir, G., Franceschini, N., Garcia, M., Gieger, C., Gislason, G. K., Grkovic, I., Hammond, C. J., Hancock, D. B., Harris, T. B., Ramasamy, A., Heckbert, S. R., Heliövaara, M., Homuth, G., Hysi, P. G., James, A. L., Jankovic, S., Joubert, B. R., Karrasch, S., Klopp, N., Koch, B., Kritchevsky, S. B., Launer, L. J., Liu, Y., Loehr, L. R., Lohman, K., Loos, R. J., Lumley, T., Al Balushi, K. A., Ang, W. Q., Barr, R. G., Beilby, J., Blakey, J. D., Boban, M., Boraska, V., Brisman, J., Britton, J. R., Brusselle, G., Cooper, C., Curjuric, I., Dahgam, S., Deary, I. J., Ebrahim, S., Eijgelsheim, M., Francks, C., Gaysina, D., Granell, R., Gu, X., Hankinson, J. L., Hardy, R., Harris, S. E., Henderson, J., Henry, A., Hingorani, A. D., Hofman, A., Holt, P. G., Hui, J., Hunter, M. L., Imboden, M., Jameson, K. A., Kerr, S. M., Kolcic, I., Kronenberg, F., Liu, J. Z., Marchini, J., McKeever, T., Morris, A. D., Olin, A. C., Porteous, D. J., Postma, D. S., Rich, S. S., Ring, S. M., Rivadeneira, F., Rochat, T., Sayer, A. A., Sayers, I., Sly, P. D., Smith, G. D., Sood, A., Starr, J. M., Uitterlinden, A. G., Vonk, J. M., Wannamethee, S. G., Whincup, P. H., Wijmenga, C., Williams, O. D., Wong, A., Mangino, M., Marciante, K. D., McArdle, W. L., Meibohm, B., Morrison, A. C., North, K. E., Omenaas, E., Palmer, L. J., Pietiläinen, K. H., Pin, I., Pola Sbreve Ek, O., Pouta, A., Psaty, B. M., Hartikainen, A. L., Rantanen, T., Ripatti, S., Rotter, J. I., Rudan, I., Rudnicka, A. R., Schulz, H., Shin, S. Y., Spector, T. D., Surakka, I., Vitart, V., Völzke, H., Wareham, N. J., Warrington, N. M., Wichmann, H. E., Wild, S. H., Wilk, J. B., Wjst, M., Wright, A. F., Zgaga, L., Zemunik, T., Pennell, C. E., Nyberg, F., Kuh, D., Holloway, J. W., Boezen, H. M., Lawlor, D. A., Morris, R. W., Probst-Hensch, N., The International Lung Cancer Consortium, Giant consortium, Kaprio, J., Wilson, J. F., Hayward, C., Kähönen, M., Heinrich, J., Musk, A. W., Jarvis, D. L., Gläser, S., Järvelin, M. R., Ch Stricker, B. H., Elliott, P., O'Connor, G. T., Strachan, D. P., London, S. J., Hall, I. P., Gudnason, V., & Tobin, M. D. (2011). Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. Nature Genetics, 43, 1082-1090. doi:10.1038/ng.941.

    Abstract

    Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
  • Dow, D. J., Huxley-Jones, J., Hall, J. M., Francks, C., Maycox, P. R., Kew, J. N., Gloger, I. S., Mehta, N. A., Kelly, F. M., Muglia, P., Breen, G., Jugurnauth, S., Pederoso, I., St.Clair, D., Rujescu, D., & Barnes, M. R. (2011). ADAMTSL3 as a candidate gene for schizophrenia: Gene sequencing and ultra-high density association analysis by imputation. Schizophrenia Research, 127(1-3), 28-34. doi:10.1016/j.schres.2010.12.009.

    Abstract

    We previously reported an association with a putative functional variant in the ADAMTSL3 gene, just below genome-wide significance in a genome-wide association study of schizophrenia. As variants impacting the function of ADAMTSL3 (a disintegrin-like and metalloprotease domain with thrombospondin type I motifs-like-3) could illuminate a novel disease mechanism and a potentially specific target, we have used complementary approaches to further evaluate the association. We imputed genotypes and performed high density association analysis using data from the HapMap and 1000 genomes projects. To review all variants that could potentially cause the association, and to identify additional possible pathogenic rare variants, we sequenced ADAMTSL3 in 92 schizophrenics. A total of 71 ADAMTSL3 variants were identified by sequencing, many were also seen in the 1000 genomes data, but 26 were novel. None of the variants identified by re-sequencing was in strong linkage disequilibrium (LD) with the associated markers. Imputation analysis refined association between ADAMTSL3 and schizophrenia, and highlighted additional common variants with similar levels of association. We evaluated the functional consequences of all variants identified by sequencing, or showing direct or imputed association. The strongest evidence for function remained with the originally associated variant, rs950169, suggesting that this variant may be causal of the association. Rare variants were also identified with possible functional impact. Our study confirms ADAMTSL3 as a candidate for further investigation in schizophrenia, using the variants identified here. The utility of imputation analysis is demonstrated, and we recommend wider use of this method to re-evaluate the existing canon of suggestive schizophrenia associations.
  • Francks, C. (2011). Leucine-rich repeat genes and the fine-tuning of synapses. Biological Psychiatry, 69, 820-821. doi:10.1016/j.biopsych.2010.12.018.
  • Ingason, A., Rujescu, D., Cichon, S., Sigurdsson, E., Sigmundsson, T., Pietilainen, O. P. H., Buizer-Voskamp, J. E., Strengman, E., Francks, C., Muglia, P., Gylfason, A., Gustafsson, O., Olason, P. I., Steinberg, S., Hansen, T., Jakobsen, K. D., Rasmussen, H. B., Giegling, I., Möller, H.-J., Hartmann, A. and 28 moreIngason, A., Rujescu, D., Cichon, S., Sigurdsson, E., Sigmundsson, T., Pietilainen, O. P. H., Buizer-Voskamp, J. E., Strengman, E., Francks, C., Muglia, P., Gylfason, A., Gustafsson, O., Olason, P. I., Steinberg, S., Hansen, T., Jakobsen, K. D., Rasmussen, H. B., Giegling, I., Möller, H.-J., Hartmann, A., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Bramon, E., Kiemeney, L. A., Franke, B., Murray, R., Vassos, E., Toulopoulou, T., Mühleisen, T. W., Tosato, S., Ruggeri, M., Djurovic, S., Andreassen, O. A., Zhang, Z., Werge, T., Ophoff, R. A., Rietschel, M., Nöthen, M. M., Petursson, H., Stefansson, H., Peltonen, L., Collier, D., Stefansson, K., & St Clair, D. M. (2011). Copy number variations of chromosome 16p13.1 region associated with schizophrenia. Molecular Psychiatry, 16, 17-25. doi:10.1038/mp.2009.101.

    Abstract

    Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35 079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P=0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.
  • Francks, C., Tozzi, F., Farmer, A., Vincent, J. B., Rujescu, D., St Clair, D., & Muglia, P. (2010). Population-based linkage analysis of schizophrenia and bipolar case-control cohorts identifies a potential susceptibility locus on 19q13. Molecular Psychiatry, 15, 319-325. doi:10.1038/mp.2008.100.

    Abstract

    Population-based linkage analysis is a new method for analysing genomewide single nucleotide polymorphism (SNP) genotype data in case-control samples, which does not assume a common disease, common variant model. The genome is scanned for extended segments that show increased identity-by-descent sharing within case-case pairs, relative to case-control or control-control pairs. The method is robust to allelic heterogeneity and is suited to mapping genes which contain multiple, rare susceptibility variants of relatively high penetrance. We analysed genomewide SNP datasets for two schizophrenia case-control cohorts, collected in Aberdeen (461 cases, 459 controls) and Munich (429 cases, 428 controls). Population-based linkage testing must be performed within homogeneous samples and it was therefore necessary to analyse the cohorts separately. Each cohort was first subjected to several procedures to improve genetic homogeneity, including identity-by-state outlier detection and multidimensional scaling analysis. When testing only cases who reported a positive family history of major psychiatric disease, consistent with a model of strongly penetrant susceptibility alleles, we saw a distinct peak on chromosome 19q in both cohorts that appeared in meta-analysis (P=0.000016) to surpass the traditional level for genomewide significance for complex trait linkage. The linkage signal was also present in a third case-control sample for familial bipolar disorder, such that meta-analysing all three datasets together yielded a linkage P=0.0000026. A model of rare but highly penetrant disease alleles may be more applicable to some instances of major psychiatric diseases than the common disease common variant model, and we therefore suggest that other genome scan datasets are analysed with this new, complementary method.
  • Ingason, A., Giegling, I., Cichon, S., Hansen, T., Rasmussen, H. B., Nielsen, J., Jurgens, G., Muglia, P., Hartmann, A. M., Strengman, E., Vasilescu, C., Muhleisen, T. W., Djurovic, S., Melle, I., Lerer, B., Möller, H.-J., Francks, C., Pietilainen, O. P. H., Lonnqvist, J., Suvisaari, J. and 20 moreIngason, A., Giegling, I., Cichon, S., Hansen, T., Rasmussen, H. B., Nielsen, J., Jurgens, G., Muglia, P., Hartmann, A. M., Strengman, E., Vasilescu, C., Muhleisen, T. W., Djurovic, S., Melle, I., Lerer, B., Möller, H.-J., Francks, C., Pietilainen, O. P. H., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Walshe, M., Vassos, E., Di Forti, M., Murray, R., Bonetto, C., Tosato, S., Cantor, R. M., Rietschel, M., Craddock, N., Owen, M. J., Andreassen, O. A., Nothen, M. M., Peltonen, L., St. Clair, D., Ophoff, R. A., O’Donovan, M. C., Collier, D. A., Werge, T., & Rujescu, D. (2010). A large replication study and meta-analysis in European samples provides further support for association of AHI1 markers with schizophrenia. Human Molecular Genetics, 19(7), 1379-1386. doi:10.1093/hmg/ddq009.

    Abstract

    The Abelson helper integration site 1 (AHI1) gene locus on chromosome 6q23 is among a group of candidate loci for schizophrenia susceptibility that were initially identified by linkage followed by linkage disequilibrium mapping, and subsequent replication of the association in an independent sample. Here, we present results of a replication study of AHI1 locus markers, previously implicated in schizophrenia, in a large European sample (in total 3907 affected and 7429 controls). Furthermore, we perform a meta-analysis of the implicated markers in 4496 affected and 18,920 controls. Both the replication study of new samples and the meta-analysis show evidence for significant overrepresentation of all tested alleles in patients compared with controls (meta-analysis; P = 8.2 x 10(-5)-1.7 x 10(-3), common OR = 1.09-1.11). The region contains two genes, AHI1 and C6orf217, and both genes-as well as the neighbouring phosphodiesterase 7B (PDE7B)-may be considered candidates for involvement in the genetic aetiology of schizophrenia.
  • Liu, J. Z., Tozzi, F., Waterworth, D. M., Pillai, S. G., Muglia, P., Middleton, L., Berrettini, W., Knouff, C. W., Yuan, X., Waeber, G., Vollenweider, P., Preisig, M., Wareham, N. J., Zhao, J. H., Loos, R. J. F., Barroso, I., Khaw, K.-T., Grundy, S., Barter, P., Mahley, R. and 86 moreLiu, J. Z., Tozzi, F., Waterworth, D. M., Pillai, S. G., Muglia, P., Middleton, L., Berrettini, W., Knouff, C. W., Yuan, X., Waeber, G., Vollenweider, P., Preisig, M., Wareham, N. J., Zhao, J. H., Loos, R. J. F., Barroso, I., Khaw, K.-T., Grundy, S., Barter, P., Mahley, R., Kesaniemi, A., McPherson, R., Vincent, J. B., Strauss, J., Kennedy, J. L., Farmer, A., McGuffin, P., Day, R., Matthews, K., Bakke, P., Gulsvik, A., Lucae, S., Ising, M., Brueckl, T., Horstmann, S., Wichmann–, H.-E., Rawal, R., Dahmen, N., Lamina, C., Polasek, O., Zgaga, L., Huffman, J., Campbell, S., Kooner, J., Chambers, J. C., Burnett, M. S., Devaney, J. M., Pichard, A. D., Kent, K. M., Satler, L., Lindsay, J. M., Waksman, R., Epstein, S., Wilson, J. F., Wild, S. H., Campbell, H., Vitart, V., Reilly, M. P., Li, M., Qu, L., Wilensky, R., Matthai, W., Hakonarson, H. H., Rader, D. J., Franke, A., Wittig, M., Schäfer, A., Uda, M., Terracciano, A., Xiao, X., Busonero, F., Scheet, P., Schlessinger, D., St. Clair, D., Rujescu, D., Abecasis, G. R., Grabe, H. J., Teumer, A., Völzke, H., Petersmann, A., John, U., Rudan, I., Hayward, C., Wright, A. F., Kolcic, I., Wright, B. J., Thompson, J. R., Balmforth, A. J., Hall, A. S., Samani, N. J., Anderson, C. A., Ahmad, T., Mathew, C. G., Parkes, M., Satsangi, J., Caulfield, M., Munroe, P. B., Farrall, M., Dominiczak, A., Worthington, J., Thomson, W., Eyre, S., Barton, A., Mooser, V., Francks, C., & Marchini, J. (2010). Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nature Genetics, 42(5), 436-440. doi:10.1038/ng.572.

    Abstract

    Smoking is a leading global cause of disease and mortality. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.
  • Muglia, P., Tozzi, F., Galwey, N. W., Francks, C., Upmanyu, R., Kong, X., Antoniades, A., Domenici, E., Perry, J., Rothen, S., Vandeleur, C. L., Mooser, V., Waeber, G., Vollenweider, P., Preisig, M., Lucae, S., Muller-Myhsok, B., Holsboer, F., Middleton, L. T., & Roses, A. D. (2010). Genome-wide association study of recurrent major depressive disorder in two European case-control cohorts. Molecular Psychiatry, 15(6), 589-601. doi:10.1038/mp.2008.131.

    Abstract

    Major depressive disorder (MDD) is a highly prevalent disorder with substantial heritability. Heritability has been shown to be substantial and higher in the variant of MDD characterized by recurrent episodes of depression. Genetic studies have thus far failed to identify clear and consistent evidence of genetic risk factors for MDD. We conducted a genome-wide association study (GWAS) in two independent datasets. The first GWAS was performed on 1022 recurrent MDD patients and 1000 controls genotyped on the Illumina 550 platform. The second was conducted on 492 recurrent MDD patients and 1052 controls selected from a population-based collection, genotyped on the Affymetrix 5.0 platform. Neither GWAS identified any SNP that achieved GWAS significance. We obtained imputed genotypes at the Illumina loci for the individuals genotyped on the Affymetrix platform, and performed a meta-analysis of the two GWASs for this common set of approximately half a million SNPs. The meta-analysis did not yield genome-wide significant results either. The results from our study suggest that SNPs with substantial odds ratio are unlikely to exist for MDD, at least in our datasets and among the relatively common SNPs genotyped or tagged by the half-million-loci arrays. Meta-analysis of larger datasets is warranted to identify SNPs with smaller effects or with rarer allele frequencies that contribute to the risk of MDD.
  • Francks, C. (2009). 13 - LRRTM1: A maternally suppressed genetic effect on handedness and schizophrenia. In I. E. C. Sommer, & R. S. Kahn (Eds.), Cerebral lateralization and psychosis (pp. 181-196). Cambridge: Cambridge University Press.

    Abstract

    The molecular, developmental, and evolutionary bases of human brain asymmetry are almost completely unknown. Genetic linkage and association mapping have pin-pointed a gene called LRRTM1 (leucine-rich repeat transmembrane neuronal 1) that may contribute to variability in human handedness. Here I describe how LRRTM1's involvement in handedness was discovered, and also the latest knowledge of its functions in brain development and disease. The association of LRRTM1 with handedness was derived entirely from the paternally inherited gene, and follow-up analysis of gene expression confirmed that LRRTM1 is one of a small number of genes that are imprinted in the human genome, for which the maternally inherited copy is suppressed. The same variation at LRRTM1 that was associated paternally with mixed-/left-handedness was also over-transmitted paternally to schizophrenic patients in a large family study. LRRTM1 is expressed in specific regions of the developing and adult forebrain by post-mitotic neurons, and the protein may be involved in axonal trafficking. Thus LRRTM1 has a probable role in neurodevelopment, and its association with handedness suggests that one of its functions may be in establishing or consolidating human brain asymmetry. LRRTM1 is the first gene for which allelic variation has been associated with human handedness. The genetic data also suggest indirectly that the epigenetic regulation of this gene may yet prove more important than DNA sequence variation for influencing brain development and disease. Intriguingly, the parent-of-origin activity of LRRTM1 suggests that men and women have had conflicting interests in relation to the outcome of lateralized brain development in their offspring.
  • Francks, C. (2009). Understanding the genetics of behavioural and psychiatric traits will only be achieved through a realistic assessment of their complexity. Laterality: Asymmetries of Body, Brain and Cognition, 14(1), 11-16. doi:10.1080/13576500802536439.

    Abstract

    Francks et al. (2007) performed a recent study in which the first putative genetic effect on human handedness was identified (the imprinted locus LRRTM1 on human chromosome 2). In this issue of Laterality, Tim Crow and colleagues present a critique of that study. The present paper presents a personal response to that critique which argues that Francks et al. (2007) published a substantial body of evidence implicating LRRTM1 in handedness and schizophrenia. Progress will now be achieved by others trying to validate, refute, or extend those findings, rather than by further armchair discussion.
  • Need, A. C., Ge, D., Weale, M. E., Maia, J., Feng, S., Heinzen, E. L., Shianna, K. V., Yoon, W., Kasperavičiūtė, D., Gennarelli, M., Strittmatter, W. J., Bonvicini, C., Rossi, G., Jayathilake, K., Cola, P. A., McEvoy, J. P., Keefe, R. S. E., Fisher, E. M. C., St. Jean, P. L., Giegling, I. and 13 moreNeed, A. C., Ge, D., Weale, M. E., Maia, J., Feng, S., Heinzen, E. L., Shianna, K. V., Yoon, W., Kasperavičiūtė, D., Gennarelli, M., Strittmatter, W. J., Bonvicini, C., Rossi, G., Jayathilake, K., Cola, P. A., McEvoy, J. P., Keefe, R. S. E., Fisher, E. M. C., St. Jean, P. L., Giegling, I., Hartmann, A. M., Möller, H.-J., Ruppert, A., Fraser, G., Crombie, C., Middleton, L. T., St. Clair, D., Roses, A. D., Muglia, P., Francks, C., Rujescu, D., Meltzer, H. Y., & Goldstein, D. B. (2009). A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genetics, 5(2), e1000373. doi:10.1371/journal.pgen.1000373.

    Abstract

    We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater “load” of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.
  • Scott, L. J., Muglia, P., Kong, X. Q., Guan, W., Flickinger, M., Upmanyu, R., Tozzi, F., Li, J. Z., Burmeister, M., Absher, D., Thompson, R. C., Francks, C., Meng, F., Antoniades, A., Southwick, A. M., Schatzberg, A. F., Bunney, W. E., Barchas, J. D., Jones, E. G., Day, R. and 13 moreScott, L. J., Muglia, P., Kong, X. Q., Guan, W., Flickinger, M., Upmanyu, R., Tozzi, F., Li, J. Z., Burmeister, M., Absher, D., Thompson, R. C., Francks, C., Meng, F., Antoniades, A., Southwick, A. M., Schatzberg, A. F., Bunney, W. E., Barchas, J. D., Jones, E. G., Day, R., Matthews, K., McGuffin, P., Strauss, J. S., Kennedy, J. L., Middleton, L., Roses, A. D., Watson, S. J., Vincent, J. B., Myers, R. M., Farmer, A. E., Akil, H., Burns, D. K., & Boehnke, M. (2009). Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry. Proceedings of the National Academy of Sciences of the United States of America, 106(18), 7501-7506. doi:10.1073/pnas.0813386106.

    Abstract

    Bipolar disorder (BP) is a disabling and often life-threatening disorder that affects approximately 1% of the population worldwide. To identify genetic variants that increase the risk of BP, we genotyped on the Illumina HumanHap550 Beadchip 2,076 bipolar cases and 1,676 controls of European ancestry from the National Institute of Mental Health Human Genetics Initiative Repository, and the Prechter Repository and samples collected in London, Toronto, and Dundee. We imputed SNP genotypes and tested for SNP-BP association in each sample and then performed meta-analysis across samples. The strongest association P value for this 2-study meta-analysis was 2.4 x 10(-6). We next imputed SNP genotypes and tested for SNP-BP association based on the publicly available Affymetrix 500K genotype data from the Wellcome Trust Case Control Consortium for 1,868 BP cases and a reference set of 12,831 individuals. A 3-study meta-analysis of 3,683 nonoverlapping cases and 14,507 extended controls on >2.3 M genotyped and imputed SNPs resulted in 3 chromosomal regions with association P approximately 10(-7): 1p31.1 (no known genes), 3p21 (>25 known genes), and 5q15 (MCTP1). The most strongly associated nonsynonymous SNP rs1042779 (OR = 1.19, P = 1.8 x 10(-7)) is in the ITIH1 gene on chromosome 3, with other strongly associated nonsynonymous SNPs in GNL3, NEK4, and ITIH3. Thus, these chromosomal regions harbor genes implicated in cell cycle, neurogenesis, neuroplasticity, and neurosignaling. In addition, we replicated the reported ANK3 association results for SNP rs10994336 in the nonoverlapping GSK sample (OR = 1.37, P = 0.042). Although these results are promising, analysis of additional samples will be required to confirm that variant(s) in these regions influence BP risk.

    Supplementary material

    Supp_Inform_Scott_et_al.pdf
  • Berrettini, W., Yuan, X., Tozzi, F., Song, K., Francks, C., Chilcoat, H., Waterworth, D., Muglia, P., & Mooser, V. (2008). Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Molecular Psychiatry, 13, 368-373. doi:10.1038/sj.mp.4002154.

    Abstract

    Twin studies indicate that additive genetic effects explain most of the variance in nicotine dependence (ND), a construct emphasizing habitual heavy smoking despite adverse consequences, tolerance and withdrawal. To detect ND alleles, we assessed cigarettes per day (CPD) regularly smoked, in two European populations via whole genome association techniques. In these approximately 7500 persons, a common haplotype in the CHRNA3-CHRNA5 nicotinic receptor subunit gene cluster was associated with CPD (nominal P=6.9 x 10(-5)). In a third set of European populations (n= approximately 7500) which had been genotyped for approximately 6000 SNPs in approximately 2000 genes, an allele in the same haplotype was associated with CPD (nominal P=2.6 x 10(-6)). These results (in three independent populations of European origin, totaling approximately 15 000 individuals) suggest that a common haplotype in the CHRNA5/CHRNA3 gene cluster on chromosome 15 contains alleles, which predispose to ND.

    Supplementary material

    Suppl.Material.doc
  • Need, A. C., Attix, D. K., McEvoy, J. M., Cirulli, E. T., Linney, K. N., Wagoner, A. P., Gumbs, C. E., Giegling, I., Möller, H.-J., Francks, C., Muglia, P., Roses, A., Gibson, G., Weale, M. E., Rujescu, D., & Goldstein, D. B. (2008). Failure to replicate effect of Kibra on human memory in two large cohorts of European origin. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 147B, 667-668. doi:10.1002/ajmg.b.30658.

    Abstract

    It was recently suggested that the Kibra polymorphism rs17070145 has a strong effect on multiple episodic memory tasks in humans. We attempted to replicate this using two cohorts of European genetic origin (n = 319 and n = 365). We found no association with either the original SNP or a set of tagging SNPs in the Kibra gene with multiple verbal memory tasks, including one that was an exact replication (Auditory Verbal Learning Task, AVLT). These results suggest that Kibra does not have a strong and general effect on human memory.

    Supplementary material

    SupplementaryMethodsIAmJMedGen.doc
  • Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O. P. H., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J. E., Hansen, T., Jakobsen, K. D., Muglia, P., Francks, C., Matthews, P. M., Gylfason, A., Halldorsson, B. V., Gudbjartsson, D., Thorgeirsson, T. E., Sigurdsson, A. and 55 moreStefansson, H., Rujescu, D., Cichon, S., Pietilainen, O. P. H., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J. E., Hansen, T., Jakobsen, K. D., Muglia, P., Francks, C., Matthews, P. M., Gylfason, A., Halldorsson, B. V., Gudbjartsson, D., Thorgeirsson, T. E., Sigurdsson, A., Jonasdottir, A., Jonasdottir, A., Bjornsson, A., Mattiasdottir, S., Blondal, T., Haraldsson, M., Magnusdottir, B. B., Giegling, I., Möller, H.-J., Hartmann, A., Shianna, K. V., Ge, D., Need, A. C., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Paunio, T., Toulopoulou, T., Bramon, E., Forti, M. D., Murray, R., Ruggeri, M., Vassos, E., Tosato, S., Walshe, M., Li, T., Vasilescu, C., Muhleisen, T. W., Wang, A. G., Ullum, H., Djurovic, S., Melle, I., Olesen, J., Kiemeney, L. A., Franke, B., Sabatti, C., Freimer, N. B., Gulcher, J. R., Thorsteinsdottir, U., Kong, A., Andreassen, O. A., Ophoff, R. A., Georgi, A., Rietschel, M., Werge, T., Petursson, H., Goldstein, D. B., Nothen, M. M., Peltonen, L., Collier, D. A., St. Clair, D., & Stefansson, K. (2008). Large recurrent microdeletions associated with schizophrenia [Letter to Nature]. Nature, 455(7210), 232-236. doi:10.1038/nature07229.

    Abstract

    Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

    Supplementary material

    Suppl.Material.pdf
  • Francks, C., Maegawa, S., Laurén, J., Abrahams, B. S., Velayos-Baeza, A., Medland, S. E., Colella, S., Groszer, M., McAuley, E. Z., Caffrey, T. M., Timmusk, T., Pruunsild, P., Koppel, I., Lind, P. A., Matsumoto-Itaba, N., Nicod, J., Xiong, L., Joober, R., Enard, W., Krinsky, B. and 22 moreFrancks, C., Maegawa, S., Laurén, J., Abrahams, B. S., Velayos-Baeza, A., Medland, S. E., Colella, S., Groszer, M., McAuley, E. Z., Caffrey, T. M., Timmusk, T., Pruunsild, P., Koppel, I., Lind, P. A., Matsumoto-Itaba, N., Nicod, J., Xiong, L., Joober, R., Enard, W., Krinsky, B., Nanba, E., Richardson, A. J., Riley, B. P., Martin, N. G., Strittmatter, S. M., Möller, H.-J., Rujescu, D., St Clair, D., Muglia, P., Roos, J. L., Fisher, S. E., Wade-Martins, R., Rouleau, G. A., Stein, J. F., Karayiorgou, M., Geschwind, D. H., Ragoussis, J., Kendler, K. S., Airaksinen, M. S., Oshimura, M., DeLisi, L. E., & Monaco, A. P. (2007). LRRTM1 on chromosome 2p12 is a maternally suppressed gene that is associated paternally with handedness and schizophrenia. Molecular Psychiatry, 12, 1129-1139. doi:10.1038/sj.mp.4002053.

    Abstract

    Left-right asymmetrical brain function underlies much of human cognition, behavior and emotion. Abnormalities of cerebral asymmetry are associated with schizophrenia and other neuropsychiatric disorders. The molecular, developmental and evolutionary origins of human brain asymmetry are unknown. We found significant association of a haplotype upstream of the gene LRRTM1 (Leucine-rich repeat transmembrane neuronal 1) with a quantitative measure of human handedness in a set of dyslexic siblings, when the haplotype was inherited paternally (P=0.00002). While we were unable to find this effect in an epidemiological set of twin-based sibships, we did find that the same haplotype is overtransmitted paternally to individuals with schizophrenia/schizoaffective disorder in a study of 1002 affected families (P=0.0014). We then found direct confirmatory evidence that LRRTM1 is an imprinted gene in humans that shows a variable pattern of maternal downregulation. We also showed that LRRTM1 is expressed during the development of specific forebrain structures, and thus could influence neuronal differentiation and connectivity. This is the first potential genetic influence on human handedness to be identified, and the first putative genetic effect on variability in human brain asymmetry. LRRTM1 is a candidate gene for involvement in several common neurodevelopmental disorders, and may have played a role in human cognitive and behavioral evolution.
  • Fisher, S. E., & Francks, C. (2006). Genes, cognition and dyslexia: Learning to read the genome. Trends in Cognitive Sciences, 10, 250-257. doi:10.1016/j.tics.2006.04.003.

    Abstract

    Studies of dyslexia provide vital insights into the cognitive architecture underpinning both disordered and normal reading. It is well established that inherited factors contribute to dyslexia susceptibility, but only very recently has evidence emerged to implicate specific candidate genes. In this article, we provide an accessible overview of four prominent examples--DYX1C1, KIAA0319, DCDC2 and ROBO1--and discuss their relevance for cognition. In each case correlations have been found between genetic variation and reading impairments, but precise risk variants remain elusive. Although none of these genes is specific to reading-related neuronal circuits, or even to the human brain, they have intriguing roles in neuronal migration or connectivity. Dissection of cognitive mechanisms that subserve reading will ultimately depend on an integrated approach, uniting data from genetic investigations, behavioural studies and neuroimaging.
  • Ogdie, M. N., Bakker, S. C., Fisher, S. E., Francks, C., Yang, M. H., Cantor, R. M., Loo, S. K., Van der Meulen, E., Pearson, P., Buitelaar, J., Monaco, A., Nelson, S. F., Sinke, R. J., & Smalley, S. L. (2006). Pooled genome-wide linkage data on 424 ADHD ASPs suggests genetic heterogeneity and a common risk locus at 5p13 [Letter to the editor]. Molecular Psychiatry, 11, 5-8. doi:10.1038/sj.mp.4001760.
  • Paracchini, S., Thomas, A., Castro, S., Lai, C., Paramasivam, M., Wang, Y., Keating, B. J., Taylor, J. M., Hacking, D. F., Scerri, T., Francks, C., Richardson, A. J., Wade-Martins, R., Stein, J. F., Knight, J. C., Copp, A. J., LoTurco, J., & Monaco, A. P. (2006). The chromosome 6p22 haplotype associated with dyslexia reduces the expression of KIAA0319, a novel gene involved in neuronal migration. Human Molecular Genetics, 15(10), 1659-1666. doi:10.1093/hmg/ddl089.

    Abstract

    Dyslexia is one of the most prevalent childhood cognitive disorders, affecting approximately 5% of school-age children. We have recently identified a risk haplotype associated with dyslexia on chromosome 6p22.2 which spans the TTRAP gene and portions of THEM2 and KIAA0319. Here we show that in the presence of the risk haplotype, the expression of the KIAA0319 gene is reduced but the expression of the other two genes remains unaffected. Using in situ hybridization, we detect a very distinct expression pattern of the KIAA0319 gene in the developing cerebral neocortex of mouse and human fetuses. Moreover, interference with rat Kiaa0319 expression in utero leads to impaired neuronal migration in the developing cerebral neocortex. These data suggest a direct link between a specific genetic background and a biological mechanism leading to the development of dyslexia: the risk haplotype on chromosome 6p22.2 down-regulates the KIAA0319 gene which is required for neuronal migration during the formation of the cerebral neocortex.
  • Gayán, J., Willcutt, E. G., Fisher, S. E., Francks, C., Cardon, L. R., Olson, R. K., Pennington, B. F., Smith, S., Monaco, A. P., & DeFries, J. C. (2005). Bivariate linkage scan for reading disability and attention-deficit/hyperactivity disorder localizes pleiotropic loci. Journal of Child Psychology and Psychiatry, 46(10), 1045-1056. doi:10.1111/j.1469-7610.2005.01447.x.

    Abstract

    BACKGROUND: There is a growing interest in the study of the genetic origins of comorbidity, a direct consequence of the recent findings of genetic loci that are seemingly linked to more than one disorder. There are several potential causes for these shared regions of linkage, but one possibility is that these loci may harbor genes with manifold effects. The established genetic correlation between reading disability (RD) and attention-deficit/hyperactivity disorder (ADHD) suggests that their comorbidity is due at least in part to genes that have an impact on several phenotypes, a phenomenon known as pleiotropy. METHODS: We employ a bivariate linkage test for selected samples that could help identify these pleiotropic loci. This linkage method was employed to carry out the first bivariate genome-wide analysis for RD and ADHD, in a selected sample of 182 sibling pairs. RESULTS: We found evidence for a novel locus at chromosome 14q32 (multipoint LOD=2.5; singlepoint LOD=3.9) with a pleiotropic effect on RD and ADHD. Another locus at 13q32, which had been implicated in previous univariate scans of RD and ADHD, seems to have a pleiotropic effect on both disorders. 20q11 is also suggested as a pleiotropic locus. Other loci previously implicated in RD or ADHD did not exhibit bivariate linkage. CONCLUSIONS: Some loci are suggested as having pleiotropic effects on RD and ADHD, while others might have unique effects. These results highlight the utility of this bivariate linkage method to study pleiotropy.
  • Francks, C., Paracchini, S., Smith, S. D., Richardson, A. J., Scerri, T. S., Cardon, L. R., Marlow, A. J., MacPhie, I. L., Walter, J., Pennington, B. F., Fisher, S. E., Olson, R. K., DeFries, J. C., Stein, J. F., & Monaco, A. P. (2004). A 77-kilobase region of chromosome 6p22.2 is associated with dyslexia in families from the United Kingdom and from the United States. American Journal of Human Genetics, 75(6), 1046-1058. doi:10.1086/426404.

    Abstract

    Several quantitative trait loci (QTLs) that influence developmental dyslexia (reading disability [RD]) have been mapped to chromosome regions by linkage analysis. The most consistently replicated area of linkage is on chromosome 6p23-21.3. We used association analysis in 223 siblings from the United Kingdom to identify an underlying QTL on 6p22.2. Our association study implicates a 77-kb region spanning the gene TTRAP and the first four exons of the neighboring uncharacterized gene KIAA0319. The region of association is also directly upstream of a third gene, THEM2. We found evidence of these associations in a second sample of siblings from the United Kingdom, as well as in an independent sample of twin-based sibships from Colorado. One main RD risk haplotype that has a frequency of ∼12% was found in both the U.K. and U.S. samples. The haplotype is not distinguished by any protein-coding polymorphisms, and, therefore, the functional variation may relate to gene expression. The QTL influences a broad range of reading-related cognitive abilities but has no significant impact on general cognitive performance in these samples. In addition, the QTL effect may be largely limited to the severe range of reading disability.
  • Loo, S. K., Fisher, S. E., Francks, C., Ogdie, M. N., MacPhie, I. L., Yang, M., McCracken, J. T., McGough, J. J., Nelson, S. F., Monaco, A. P., & Smalley, S. L. (2004). Genome-wide scan of reading ability in affected sibling pairs with attention-deficit/hyperactivity disorder: Unique and shared genetic effects. Molecular Psychiatry, 9, 485-493. doi:10.1038/sj.mp.4001450.

    Abstract

    Attention-deficit/hyperactivity disorder (ADHD) and reading disability (RD) are common highly heritable disorders of childhood, which frequently co-occur. Data from twin and family studies suggest that this overlap is, in part, due to shared genetic underpinnings. Here, we report the first genome-wide linkage analysis of measures of reading ability in children with ADHD, using a sample of 233 affected sibling pairs who previously participated in a genome-wide scan for susceptibility loci in ADHD. Quantitative trait locus (QTL) analysis of a composite reading factor defined from three highly correlated reading measures identified suggestive linkage (multipoint maximum lod score, MLS>2.2) in four chromosomal regions. Two regions (16p, 17q) overlap those implicated by our previous genome-wide scan for ADHD in the same sample: one region (2p) provides replication for an RD susceptibility locus, and one region (10q) falls approximately 35 cM from a modestly highlighted region in an independent genome-wide scan of siblings with ADHD. Investigation of an individual reading measure of Reading Recognition supported linkage to putative RD susceptibility regions on chromosome 8p (MLS=2.4) and 15q (MLS=1.38). Thus, the data support the existence of genetic factors that have pleiotropic effects on ADHD and reading ability--as suggested by shared linkages on 16p, 17q and possibly 10q--but also those that appear to be unique to reading--as indicated by linkages on 2p, 8p and 15q that coincide with those previously found in studies of RD. Our study also suggests that reading measures may represent useful phenotypes in ADHD research. The eventual identification of genes underlying these unique and shared linkages may increase our understanding of ADHD, RD and the relationship between the two.
  • Ogdie, M. N., Fisher, S. E., Yang, M., Ishii, J., Francks, C., Loo, S. K., Cantor, R. M., McCracken, J. T., McGough, J. J., Smalley, S. L., & Nelson, S. F. (2004). Attention Deficit Hyperactivity Disorder: Fine mapping supports linkage to 5p13, 6q12, 16p13, and 17p11. American Journal of Human Genetics, 75(4), 661-668. doi:10.1086/424387.

    Abstract

    We completed fine mapping of nine positional candidate regions for attention-deficit/hyperactivity disorder (ADHD) in an extended population sample of 308 affected sibling pairs (ASPs), constituting the largest linkage sample of families with ADHD published to date. The candidate chromosomal regions were selected from all three published genomewide scans for ADHD, and fine mapping was done to comprehensively validate these positional candidate regions in our sample. Multipoint maximum LOD score (MLS) analysis yielded significant evidence of linkage on 6q12 (MLS 3.30; empiric P=.024) and 17p11 (MLS 3.63; empiric P=.015), as well as suggestive evidence on 5p13 (MLS 2.55; empiric P=.091). In conjunction with the previously reported significant linkage on the basis of fine mapping 16p13 in the same sample as this report, the analyses presented here indicate that four chromosomal regions—5p13, 6q12, 16p13, and 17p11—are likely to harbor susceptibility genes for ADHD. The refinement of linkage within each of these regions lays the foundation for subsequent investigations using association methods to detect risk genes of moderate effect size.
  • Scerri, T. S., Fisher, S. E., Francks, C., MacPhie, I. L., Paracchini, S., Richardson, A. J., Stein, J. F., & Monaco, A. P. (2004). Putative functional alleles of DYX1C1 are not associated with dyslexia susceptibility in a large sample of sibling pairs from the UK [Letter to JMG]. Journal of Medical Genetics, 41(11), 853-857. doi:10.1136/jmg.2004.018341.
  • Francks, C., Fisher, S. E., Marlow, A. J., MacPhie, I. L., Taylor, K. E., Richardson, A. J., Stein, J. F., & Monaco, A. P. (2003). Familial and genetic effects on motor coordination, laterality, and reading-related cognition. American Journal of Psychiatry, 160(11), 1970-1977. doi:10.1176/appi.ajp.160.11.1970.

    Abstract

    OBJECTIVE: Recent research has provided evidence for a genetically mediated association between language or reading-related cognitive deficits and impaired motor coordination. Other studies have identified relationships between lateralization of hand skill and cognitive abilities. With a large sample, the authors aimed to investigate genetic relationships between measures of reading-related cognition, hand motor skill, and hand skill lateralization. METHOD: The authors applied univariate and bivariate correlation and familiality analyses to a range of measures. They also performed genomewide linkage analysis of hand motor skill in a subgroup of 195 sibling pairs. RESULTS: Hand motor skill was significantly familial (maximum heritability=41%), as were reading-related measures. Hand motor skill was weakly but significantly correlated with reading-related measures, such as nonword reading and irregular word reading. However, these correlations were not significantly familial in nature, and the authors did not observe linkage of hand motor skill to any chromosomal regions implicated in susceptibility to dyslexia. Lateralization of hand skill was not correlated with reading or cognitive ability. CONCLUSIONS: The authors confirmed a relationship between lower motor ability and poor reading performance. However, the genetic effects on motor skill and reading ability appeared to be largely or wholly distinct, suggesting that the correlation between these traits may have arisen from environmental influences. Finally, the authors found no evidence that reading disability and/or low general cognitive ability were associated with ambidexterity.
  • Francks, C., DeLisi, L. E., Shaw, S. H., Fisher, S. E., Richardson, A. J., Stein, J. F., & Monaco, A. P. (2003). Parent-of-origin effects on handedness and schizophrenia susceptibility on chromosome 2p12-q11. Human Molecular Genetics, 12(24), 3225-3230. doi:10.1093/hmg/ddg362.

    Abstract

    Schizophrenia and non-right-handedness are moderately associated, and both traits are often accompanied by abnormalities of asymmetrical brain morphology or function. We have found linkage previously of chromosome 2p12-q11 to a quantitative measure of handedness, and we have also found linkage of schizophrenia/schizoaffective disorder to this same chromosomal region in a separate study. Now, we have found that in one of our samples (191 reading-disabled sibling pairs), the relative hand skill of siblings was correlated more strongly with paternal than maternal relative hand skill. This led us to re-analyse 2p12-q11 under parent-of-origin linkage models. We found linkage of relative hand skill in the RD siblings to 2p12-q11 with P=0.0000037 for paternal identity-by-descent sharing, whereas the maternally inherited locus was not linked to the trait (P>0.2). Similarly, in affected-sib-pair analysis of our schizophrenia dataset (241 sibling pairs), we found linkage to schizophrenia for paternal sharing with LOD=4.72, P=0.0000016, within 3 cM of the peak linkage to relative hand skill. Maternal linkage across the region was weak or non-significant. These similar paternal-specific linkages suggest that the causative genetic effects on 2p12-q11 are related. The linkages may be due to a single maternally imprinted influence on lateralized brain development that contains common functional polymorphisms.
  • Francks, C., DeLisi, L. E., Fisher, S. E., Laval, S. H., Rue, J. E., Stein, J. F., & Monaco, A. P. (2003). Confirmatory evidence for linkage of relative hand skill to 2p12-q11 [Letter to the editor]. American Journal of Human Genetics, 72(2), 499-502. doi:10.1086/367548.
  • Marlow, A. J., Fisher, S. E., Francks, C., MacPhie, I. L., Cherny, S. S., Richardson, A. J., Talcott, J. B., Stein, J. F., Monaco, A. P., & Cardon, L. R. (2003). Use of multivariate linkage analysis for dissection of a complex cognitive trait. American Journal of Human Genetics, 72(3), 561-570. doi:10.1086/368201.

    Abstract

    Replication of linkage results for complex traits has been exceedingly difficult, owing in part to the inability to measure the precise underlying phenotype, small sample sizes, genetic heterogeneity, and statistical methods employed in analysis. Often, in any particular study, multiple correlated traits have been collected, yet these have been analyzed independently or, at most, in bivariate analyses. Theoretical arguments suggest that full multivariate analysis of all available traits should offer more power to detect linkage; however, this has not yet been evaluated on a genomewide scale. Here, we conduct multivariate genomewide analyses of quantitative-trait loci that influence reading- and language-related measures in families affected with developmental dyslexia. The results of these analyses are substantially clearer than those of previous univariate analyses of the same data set, helping to resolve a number of key issues. These outcomes highlight the relevance of multivariate analysis for complex disorders for dissection of linkage results in correlated traits. The approach employed here may aid positional cloning of susceptibility genes in a wide spectrum of complex traits.
  • Ogdie, M. N., MacPhie, I. L., Minassian, S. L., Yang, M., Fisher, S. E., Francks, C., Cantor, R. M., McCracken, J. T., McGough, J. J., Nelson, S. F., Monaco, A. P., & Smalley, S. L. (2003). A genomewide scan for Attention-Deficit/Hyperactivity Disorder in an extended sample: Suggestive linkage on 17p11. American Journal of Human Genetics, 72(5), 1268-1279. doi:10.1086/375139.

    Abstract

    Attention-deficit/hyperactivity disorder (ADHD [MIM 143465]) is a common, highly heritable neurobehavioral disorder of childhood onset, characterized by hyperactivity, impulsivity, and/or inattention. As part of an ongoing study of the genetic etiology of ADHD, we have performed a genomewide linkage scan in 204 nuclear families comprising 853 individuals and 270 affected sibling pairs (ASPs). Previously, we reported genomewide linkage analysis of a “first wave” of these families composed of 126 ASPs. A follow-up investigation of one region on 16p yielded significant linkage in an extended sample. The current study extends the original sample of 126 ASPs to 270 ASPs and provides linkage analyses of the entire sample, using polymorphic microsatellite markers that define an ∼10-cM map across the genome. Maximum LOD score (MLS) analysis identified suggestive linkage for 17p11 (MLS=2.98) and four nominal regions with MLS values >1.0, including 5p13, 6q14, 11q25, and 20q13. These data, taken together with the fine mapping on 16p13, suggest two regions as highly likely to harbor risk genes for ADHD: 16p13 and 17p11. Interestingly, both regions, as well as 5p13, have been highlighted in genomewide scans for autism.
  • Fisher, S. E., Francks, C., Marlow, A. J., MacPhie, I. L., Newbury, D. F., Cardon, L. R., Ishikawa-Brush, Y., Richardson, A. J., Talcott, J. B., Gayán, J., Olson, R. K., Pennington, B. F., Smith, S. D., DeFries, J. C., Stein, J. F., & Monaco, A. P. (2002). Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia. Nature Genetics, 30(1), 86-91. doi:10.1038/ng792.

    Abstract

    Developmental dyslexia is defined as a specific and significant impairment in reading ability that cannot be explained by deficits in intelligence, learning opportunity, motivation or sensory acuity. It is one of the most frequently diagnosed disorders in childhood, representing a major educational and social problem. It is well established that dyslexia is a significantly heritable trait with a neurobiological basis. The etiological mechanisms remain elusive, however, despite being the focus of intensive multidisciplinary research. All attempts to map quantitative-trait loci (QTLs) influencing dyslexia susceptibility have targeted specific chromosomal regions, so that inferences regarding genetic etiology have been made on the basis of very limited information. Here we present the first two complete QTL-based genome-wide scans for this trait, in large samples of families from the United Kingdom and United States. Using single-point analysis, linkage to marker D18S53 was independently identified as being one of the most significant results of the genome in each scan (P< or =0.0004 for single word-reading ability in each family sample). Multipoint analysis gave increased evidence of 18p11.2 linkage for single-word reading, yielding top empirical P values of 0.00001 (UK) and 0.0004 (US). Measures related to phonological and orthographic processing also showed linkage at this locus. We replicated linkage to 18p11.2 in a third independent sample of families (from the UK), in which the strongest evidence came from a phoneme-awareness measure (most significant P value=0.00004). A combined analysis of all UK families confirmed that this newly discovered 18p QTL is probably a general risk factor for dyslexia, influencing several reading-related processes. This is the first report of QTL-based genome-wide scanning for a human cognitive trait.
  • Fisher, S. E., Francks, C., McCracken, J. T., McGough, J. J., Marlow, A. J., MacPhie, I. L., Newbury, D. F., Crawford, L. R., Palmer, C. G. S., Woodward, J. A., Del’Homme, M., Cantwell, D. P., Nelson, S. F., Monaco, A. P., & Smalley, S. L. (2002). A genomewide scan for loci involved in Attention-Deficit/Hyperactivity Disorder. American Journal of Human Genetics, 70(5), 1183-1196. doi:10.1086/340112.

    Abstract

    Attention deficit/hyperactivity disorder (ADHD) is a common heritable disorder with a childhood onset. Molecular genetic studies of ADHD have previously focused on examining the roles of specific candidate genes, primarily those involved in dopaminergic pathways. We have performed the first systematic genomewide linkage scan for loci influencing ADHD in 126 affected sib pairs, using a ∼10-cM grid of microsatellite markers. Allele-sharing linkage methods enabled us to exclude any loci with a λs of ⩾3 from 96% of the genome and those with a λs of ⩾2.5 from 91%, indicating that there is unlikely to be a major gene involved in ADHD susceptibility in our sample. Under a strict diagnostic scheme we could exclude all screened regions of the X chromosome for a locus-specific λs of ⩾2 in brother-brother pairs, demonstrating that the excess of affected males with ADHD is probably not attributable to a major X-linked effect. Qualitative trait maximum LOD score analyses pointed to a number of chromosomal sites that may contain genetic risk factors of moderate effect. None exceeded genomewide significance thresholds, but LOD scores were >1.5 for regions on 5p12, 10q26, 12q23, and 16p13. Quantitative-trait analysis of ADHD symptom counts implicated a region on 12p13 (maximum LOD 2.6) that also yielded a LOD >1 when qualitative methods were used. A survey of regions containing 36 genes that have been proposed as candidates for ADHD indicated that 29 of these genes, including DRD4 and DAT1, could be excluded for a λs of 2. Only three of the candidates—DRD5, 5HTT, and CALCYON—coincided with sites of positive linkage identified by our screen. Two of the regions highlighted in the present study, 2q24 and 16p13, coincided with the top linkage peaks reported by a recent genome-scan study of autistic sib pairs.
  • Francks, C., Fisher, S. E., Olson, R. K., Pennington, B. F., Smith, S. D., DeFries, J. C., & Monaco, A. P. (2002). Fine mapping of the chromosome 2p12-16 dyslexia susceptibility locus: Quantitative association analysis and positional candidate genes SEMA4F and OTX1. Psychiatric Genetics, 12(1), 35-41.

    Abstract

    A locus on chromosome 2p12-16 has been implicated in dyslexia susceptibility by two independent linkage studies, including our own study of 119 nuclear twin-based families, each with at least one reading-disabled child. Nonetheless, no variant of any gene has been reported to show association with dyslexia, and no consistent clinical evidence exists to identify candidate genes with any strong a priori logic. We used 21 microsatellite markers spanning 2p12-16 to refine our 1-LOD unit linkage support interval to 12cM between D2S337 and D2S286. Then, in quantitative association analysis, two microsatellites yielded P values<0.05 across a range of reading-related measures (D2S2378 and D2S2114). The exon/intron borders of two positional candidate genes within the region were characterized, and the exons were screened for polymorphisms. The genes were Semaphorin4F (SEMA4F), which encodes a protein involved in axonal growth cone guidance, and OTX1, encoding a homeodomain transcription factor involved in forebrain development. Two non-synonymous single nucleotide polymorphisms were found in SEMA4F, each with a heterozygosity of 0.03. One intronic single nucleotide polymorphism between exons 12 and 13 of SEMA4F was tested for quantitative association, but no significant association was found. Only one single nucleotide polymorphism was found in OTX1, which was exonic but silent. Our data therefore suggest that linkage with reading disability at 2p12-16 is not caused by coding variants of SEMA4F or OTX1. Our study outlines the approach necessary for the identification of genetic variants causing dyslexia susceptibility in an epidemiological population of dyslexics.
  • Francks, C., MacPhie, I. L., & Monaco, A. P. (2002). The genetic basis of dyslexia. The Lancet Neurology, 1(8), 483-490. doi:10.1016/S1474-4422(02)00221-1.

    Abstract

    Dyslexia, a disorder of reading and spelling, is a heterogeneous neurological syndrome with a complex genetic and environmental aetiology. People with dyslexia differ in their individual profiles across a range of cognitive, physiological, and behavioural measures related to reading disability. Some or all of the subtypes of dyslexia might have partly or wholly distinct genetic causes. An understanding of the role of genetics in dyslexia could help to diagnose and treat susceptible children more effectively and rapidly than is currently possible and in ways that account for their individual disabilities. This knowledge will also give new insights into the neurobiology of reading and language cognition. Genetic linkage analysis has identified regions of the genome that might harbour inherited variants that cause reading disability. In particular, loci on chromosomes 6 and 18 have shown strong and replicable effects on reading abilities. These genomic regions contain tens or hundreds of candidate genes, and studies aimed at the identification of the specific causal genetic variants are underway.
  • Francks, C., Fisher, S. E., MacPhie, I. L., Richardson, A. J., Marlow, A. J., Stein, J. F., & Monaco, A. P. (2002). A genomewide linkage screen for relative hand skill in sibling pairs. American Journal of Human Genetics, 70(3), 800-805. doi:10.1086/339249.

    Abstract

    Genomewide quantitative-trait locus (QTL) linkage analysis was performed using a continuous measure of relative hand skill (PegQ) in a sample of 195 reading-disabled sibling pairs from the United Kingdom. This was the first genomewide screen for any measure related to handedness. The mean PegQ in the sample was equivalent to that of normative data, and PegQ was not correlated with tests of reading ability (correlations between −0.13 and 0.05). Relative hand skill could therefore be considered normal within the sample. A QTL on chromosome 2p11.2-12 yielded strong evidence for linkage to PegQ (empirical P=.00007), and another suggestive QTL on 17p11-q23 was also identified (empirical P=.002). The 2p11.2-12 locus was further analyzed in an independent sample of 143 reading-disabled sibling pairs, and this analysis yielded an empirical P=.13. Relative hand skill therefore is probably a complex multifactorial phenotype with a heterogeneous background, but nevertheless is amenable to QTL-based gene-mapping approaches.
  • Marlow, A. J., Fisher, S. E., Richardson, A. J., Francks, C., Talcott, J. B., Monaco, A. P., Stein, J. F., & Cardon, L. R. (2002). Investigation of quantitative measures related to reading disability in a large sample of sib-pairs from the UK. Behavior Genetics, 31(2), 219-230. doi:10.1023/A:1010209629021.

    Abstract

    We describe a family-based sample of individuals with reading disability collected as part of a quantitative trait loci (QTL) mapping study. Eighty-nine nuclear families (135 independent sib-pairs) were identified through a single proband using a traditional discrepancy score of predicted/actual reading ability and a known family history. Eight correlated psychometric measures were administered to each sibling, including single word reading, spelling, similarities, matrices, spoonerisms, nonword and irregular word reading, and a pseudohomophone test. Summary statistics for each measure showed a reduced mean for the probands compared to the co-sibs, which in turn was lower than that of the population. This partial co-sib regression back to the mean indicates that the measures are influenced by familial factors and therefore, may be suitable for a mapping study. The variance of each of the measures remained largely unaffected, which is reassuring for the application of a QTL approach. Multivariate genetic analysis carried out to explore the relationship between the measures identified a common factor between the reading measures that accounted for 54% of the variance. Finally the familiality estimates (range 0.32–0.73) obtained for the reading measures including the common factor (0.68) supported their heritability. These findings demonstrate the viability of this sample for QTL mapping, and will assist in the interpretation of any subsequent linkage findings in an ongoing genome scan.
  • Smalley, S. L., Kustanovich, V., Minassian, S. L., Stone, J. L., Ogdie, M. N., McGough, J. J., McCracken, J. T., MacPhie, I. L., Francks, C., Fisher, S. E., Cantor, R. M., Monaco, A. P., & Nelson, S. F. (2002). Genetic linkage of Attention-Deficit/Hyperactivity Disorder on chromosome 16p13, in a region implicated in autism. American Journal of Human Genetics, 71(4), 959-963. doi:10.1086/342732.

    Abstract

    Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed behavioral disorder in childhood and likely represents an extreme of normal behavior. ADHD significantly impacts learning in school-age children and leads to impaired functioning throughout the life span. There is strong evidence for a genetic etiology of the disorder, although putative alleles, principally in dopamine-related pathways suggested by candidate-gene studies, have very small effect sizes. We use affected-sib-pair analysis in 203 families to localize the first major susceptibility locus for ADHD to a 12-cM region on chromosome 16p13 (maximum LOD score 4.2; P=.000005), building upon an earlier genomewide scan of this disorder. The region overlaps that highlighted in three genome scans for autism, a disorder in which inattention and hyperactivity are common, and physically maps to a 7-Mb region on 16p13. These findings suggest that variations in a gene on 16p13 may contribute to common deficits found in both ADHD and autism.
  • Francks, C., Fisher, S. E., J.Marlow, A., J.Richardson, A., Stein, J. F., & Monaco, A. (2000). A sibling-pair based approach for mapping genetic loci that influence quantitative measures of reading disability. Prostaglandins, Leukotrienes and Essential Fatty Acids, 63(1-2), 27-31. doi:10.1054/plef.2000.0187.

    Abstract

    Family and twin studies consistently demonstrate a significant role for genetic factors in the aetiology of the reading disorder dyslexia. However, dyslexia is complex at both the genetic and phenotypic levels, and currently the nature of the core deficit or deficits remains uncertain. Traditional approaches for mapping disease genes, originally developed for single-gene disorders, have limited success when there is not a simple relationship between genotype and phenotype. Recent advances in high-throughput genotyping technology and quantitative statistical methods have made a new approach to identifying genes involved in complex disorders possible. The method involves assessing the genetic similarity of many sibling pairs along the lengths of all their chromosomes and attempting to correlate this similarity with that of their phenotypic scores. We are adopting this approach in an ongoing genome-wide search for genes involved in dyslexia susceptibility, and have already successfully applied the method by replicating results from previous studies suggesting that a quantitative trait locus at 6p21.3 influences reading disability.
  • Bailey, A., Hervas, A., Matthews, N., Palferman, S., Wallace, S., Aubin, A., Michelotti, J., Wainhouse, C., Papanikolaou, K., Rutter, M., Maestrini, E., Marlow, A., Weeks, D. E., Lamb, J., Francks, C., Kearsley, G., Scudder, P., Monaco, A. P., Baird, G., Cox, A. and 46 moreBailey, A., Hervas, A., Matthews, N., Palferman, S., Wallace, S., Aubin, A., Michelotti, J., Wainhouse, C., Papanikolaou, K., Rutter, M., Maestrini, E., Marlow, A., Weeks, D. E., Lamb, J., Francks, C., Kearsley, G., Scudder, P., Monaco, A. P., Baird, G., Cox, A., Cockerill, H., Nuffield, F., Le Couteur, A., Berney, T., Cooper, H., Kelly, T., Green, J., Whittaker, J., Gilchrist, A., Bolton, P., Schönewald, A., Daker, M., Ogilvie, C., Docherty, Z., Deans, Z., Bolton, B., Packer, R., Poustka, F., Rühl, D., Schmötzer, G., Bölte, S., Klauck, S. M., Spieler, A., Poustka., A., Van Engeland, H., Kemner, C., De Jonge, M., Den Hartog, I., Lord, C., Cook, E., Leventhal, B., Volkmar, F., Pauls, D., Klin, A., Smalley, S., Fombonne, E., Rogé, B., Tauber, M., Arti-Vartayan, E., Fremolle-Kruck., J., Pederson, L., Haracopos, D., Brondum-Nielsen, K., & Cotterill, R. (1998). A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium. Human Molecular Genetics, 7(3), 571-578. doi:10.1093/hmg/7.3.571.

    Abstract

    Autism is characterized by impairments in reciprocal social interaction and communication, and restricted and sterotyped patterns of interests and activities. Developmental difficulties are apparent before 3 years of age and there is evidence for strong genetic influences most likely involving more than one susceptibility gene. A two-stage genome search for susceptibility loci in autism was performed on 87 affected sib pairs plus 12 non-sib affected relative-pairs, from a total of 99 families identified by an international consortium. Regions on six chromosomes (4, 7, 10, 16, 19 and 22) were identified which generated a multipoint maximum lod score (MLS) > 1. A region on chromosome 7q was the most significant with an MLS of 3.55 near markers D7S530 and D7S684 in the subset of 56 UK affected sib-pair families, and an MLS of 2.53 in all 87 affected sib-pair families. An area on chromosome 16p near the telomere was the next most significant, with an MLS of 1.97 in the UK families, and 1.51 in all families. These results are an important step towards identifying genes predisposing to autism; establishing their general applicability requires further study.

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