Clyde Francks

Publications

Displaying 1 - 13 of 13
  • Carrion Castillo, A., Estruch, S. B., Maassen, B., Franke, B., Francks, C., & Fisher, S. E. (2021). Whole-genome sequencing identifies functional noncoding variation in SEMA3C that cosegregates with dyslexia in a multigenerational family. Human Genetics, 140, 1183-1200. doi:10.1007/s00439-021-02289-w.

    Abstract

    Dyslexia is a common heritable developmental disorder involving impaired reading abilities. Its genetic underpinnings are thought to be complex and heterogeneous, involving common and rare genetic variation. Multigenerational families segregating apparent monogenic forms of language-related disorders can provide useful entrypoints into biological pathways. In the present study, we performed a genome-wide linkage scan in a three-generational family in which dyslexia affects 14 of its 30 members and seems to be transmitted with an autosomal dominant pattern of inheritance. We identified a locus on chromosome 7q21.11 which cosegregated with dyslexia status, with the exception of two cases of phenocopy (LOD = 2.83). Whole-genome sequencing of key individuals enabled the assessment of coding and noncoding variation in the family. Two rare single-nucleotide variants (rs144517871 and rs143835534) within the first intron of the SEMA3C gene cosegregated with the 7q21.11 risk haplotype. In silico characterization of these two variants predicted effects on gene regulation, which we functionally validated for rs144517871 in human cell lines using luciferase reporter assays. SEMA3C encodes a secreted protein that acts as a guidance cue in several processes, including cortical neuronal migration and cellular polarization. We hypothesize that these intronic variants could have a cis-regulatory effect on SEMA3C expression, making a contribution to dyslexia susceptibility in this family.
  • Gialluisi, A., Andlauer, T. F. M., Mirza-Schreiber, N., Moll, K., Becker, J., Hoffmann, P., Ludwig, K. U., Czamara, D., St Pourcain, B., Honbolygó, F., Tóth, D., Csépe, V., Huguet, H., Chaix, Y., Iannuzzi, S., Demonet, J.-F., Morris, A. P., Hulslander, J., Willcutt, E. G., DeFries, J. C. and 29 moreGialluisi, A., Andlauer, T. F. M., Mirza-Schreiber, N., Moll, K., Becker, J., Hoffmann, P., Ludwig, K. U., Czamara, D., St Pourcain, B., Honbolygó, F., Tóth, D., Csépe, V., Huguet, H., Chaix, Y., Iannuzzi, S., Demonet, J.-F., Morris, A. P., Hulslander, J., Willcutt, E. G., DeFries, J. C., Olson, R. K., Smith, S. D., Pennington, B. F., Vaessen, A., Maurer, U., Lyytinen, H., Peyrard-Janvid, M., Leppänen, P. H. T., Brandeis, D., Bonte, M., Stein, J. F., Talcott, J. B., Fauchereau, F., Wilcke, A., Kirsten, H., Müller, B., Francks, C., Bourgeron, T., Monaco, A. P., Ramus, F., Landerl, K., Kere, J., Scerri, T. S., Paracchini, S., Fisher, S. E., Schumacher, J., Nöthen, M. M., Müller-Myhsok, B., & Schulte-Körne, G. (2021). Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia. Molecular Psychiatry, 26, 3004-3017. doi:10.1038/s41380-020-00898-x.

    Abstract

    Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40–60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p  < 2.8 × 10−6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20–25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p  = 8 × 10−13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10−43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10−22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10−12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10−4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10−7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10−29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.
  • Kong, X., Postema, M., Schijven, D., Carrion Castillo, A., Pepe, A., Crivello, F., Joliot, M., Mazoyer, B., Fisher, S. E., & Francks, C. (2021). Large-scale phenomic and genomic analysis of brain asymmetrical skew. Cerebral Cortex, 31(9), 4151-4168. doi:10.1093/cercor/bhab075.

    Abstract

    The human cerebral hemispheres show a left–right asymmetrical torque pattern, which has been claimed to be absent in chimpanzees. The functional significance and developmental mechanisms are unknown. Here, we carried out the largest-ever analysis of global brain shape asymmetry in magnetic resonance imaging data. Three population datasets were used, UK Biobank (N = 39 678), Human Connectome Project (N = 1113), and BIL&GIN (N = 453). At the population level, there was an anterior and dorsal skew of the right hemisphere, relative to the left. Both skews were associated independently with handedness, and various regional gray and white matter metrics oppositely in the two hemispheres, as well as other variables related to cognitive functions, sociodemographic factors, and physical and mental health. The two skews showed single nucleotide polymorphisms-based heritabilities of 4–13%, but also substantial polygenicity in causal mixture model analysis, and no individually significant loci were found in genome-wide association studies for either skew. There was evidence for a significant genetic correlation between horizontal brain skew and autism, which requires future replication. These results provide the first large-scale description of population-average brain skews and their inter-individual variations, their replicable associations with handedness, and insights into biological and other factors which associate with human brain asymmetry.
  • Postema, M., Hoogman, M., Ambrosino, S., Asherson, P., Banaschewski, T., Bandeira, C. E., Baranov, A., Bau, C. H. D., Baumeister, S., Baur-Streubel, R., Bellgrove, M. A., Biederman, J., Bralten, J., Brandeis, D., Brem, S., Buitelaar, J. K., Busatto, G. F., Castellanos, F. X., Cercignani, M., Chaim-Avancini, T. M. and 85 morePostema, M., Hoogman, M., Ambrosino, S., Asherson, P., Banaschewski, T., Bandeira, C. E., Baranov, A., Bau, C. H. D., Baumeister, S., Baur-Streubel, R., Bellgrove, M. A., Biederman, J., Bralten, J., Brandeis, D., Brem, S., Buitelaar, J. K., Busatto, G. F., Castellanos, F. X., Cercignani, M., Chaim-Avancini, T. M., Chantiluke, K. C., Christakou, A., Coghill, D., Conzelmann, A., Cubillo, A. I., Cupertino, R. B., De Zeeuw, P., Doyle, A. E., Durston, S., Earl, E. A., Epstein, J. N., Ethofer, T., Fair, D. A., Fallgatter, A. J., Faraone, S. V., Frodl, T., Gabel, M. C., Gogberashvili, T., Grevet, E. H., Haavik, J., Harrison, N. A., Hartman, C. A., Heslenfeld, D. J., Hoekstra, P. J., Hohmann, S., Høvik, M. F., Jernigan, T. L., Kardatzki, B., Karkashadze, G., Kelly, C., Kohls, G., Konrad, K., Kuntsi, J., Lazaro, L., Lera-Miguel, S., Lesch, K.-P., Louza, M. R., Lundervold, A. J., Malpas, C. B., Mattos, P., McCarthy, H., Namazova-Baranova, L., Nicolau, R., Nigg, J. T., Novotny, S. E., Oberwelland Weiss, E., O'Gorman Tuura, R. L., Oosterlaan, J., Oranje, B., Paloyelis, Y., Pauli, P., Picon, F. A., Plessen, K. J., Ramos-Quiroga, J. A., Reif, A., Reneman, L., Rosa, P. G. P., Rubia, K., Schrantee, A., Schweren, L. J. S., Seitz, J., Shaw, P., Silk, T. J., Skokauskas, N., Soliva Vila, J. C., Stevens, M. C., Sudre, G., Tamm, L., Tovar-Moll, F., Van Erp, T. G. M., Vance, A., Vilarroya, O., Vives-Gilabert, Y., Von Polier, G. G., Walitza, S., Yoncheva, Y. N., Zanetti, M. V., Ziegler, G. C., Glahn, D. C., Jahanshad, N., Medland, S. E., ENIGMA ADHD Working Group, Thompson, P. M., Fisher, S. E., Franke, B., & Francks, C. (2021). Analysis of structural brain asymmetries in Attention-Deficit/Hyperactivity Disorder in 39 datasets. Journal of Child Psychology and Psychiatry, 62(10), 1202-1219. doi:10.1111/jcpp.13396.

    Abstract

    Objective: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here we performed the largest-ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium.
    Methods: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modelling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries.
    Results: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t=2.1, P=0.04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t=2.7, P=0.01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing.
    Conclusion: Prior studies of altered structural brain asymmetry in ADHD were likely under-powered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.

    Additional information

    jcpp13396-sup-0001-supinfo.pdf
  • Sha, Z., Schijven, D., & Francks, C. (2021). Patterns of brain asymmetry associated with polygenic risks for autism and schizophrenia implicate language and executive functions but not brain masculinization. Molecular Psychiatry, 26(12), 7652-7660. doi:10.1038/s41380-021-01204-z.

    Abstract

    Autism spectrum disorder (ASD) and schizophrenia have been conceived as partly opposing disorders in terms of systemizing versus empathizing cognitive styles, with resemblances to male versus female average sex differences. Left-right asymmetry of the brain is an important aspect of its organization that shows average differences between the sexes, and can be altered in both ASD and schizophrenia. Here we mapped multivariate associations of polygenic risk scores for ASD and schizophrenia with asymmetries of regional cerebral cortical surface area, thickness and subcortical volume measures in 32,256 participants from the UK Biobank. Polygenic risks for the two disorders were positively correlated (r=0.08, p=7.13×10-50), and both were higher in females compared to males, consistent with biased participation against higher-risk males. Each polygenic risk score was associated with multivariate brain asymmetry after adjusting for sex, ASD r=0.03, p=2.17×10-9, schizophrenia r=0.04, p=2.61×10-11, but the multivariate patterns were mostly distinct for the two polygenic risks, and neither resembled average sex differences. Annotation based on meta-analyzed functional imaging data showed that both polygenic risks were associated with asymmetries of regions important for language and executive functions, consistent with behavioural associations that arose in phenome-wide association analysis. Overall, the results indicate that distinct patterns of subtly altered brain asymmetry may be functionally relevant manifestations of polygenic risks for ASD and schizophrenia, but do not support brain masculinization or feminization in their etiologies.
  • Sha, Z., Pepe, A., Schijven, D., Carrion Castillo, A., Roe, J. M., Westerhausen, R., Joliot, M., Fisher, S. E., Crivello, F., & Francks, C. (2021). Handedness and its genetic influences are associated with structural asymmetries of the cerebral cortex in 31,864 individuals. Proceedings of the National Academy of Sciences of the United States of America, 118(47): e2113095118. doi:10.1073/pnas.2113095118.

    Abstract

    Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We resampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Left-handers compared to right-handers showed average differences of surface area asymmetry within the fusiform cortex, the anterior insula, the anterior middle cingulate cortex, and the precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB, TUBA1B, TUBB3, TUBB4A, MAP2, and NME7—mutations in the latter can cause left to right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in left-handedness: on the postcentral gyrus and the inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas nonheritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference.
  • Sha, Z., Schijven, D., Carrion Castillo, A., Joliot, M., Mazoyer, B., Fisher, S. E., Crivello, F., & Francks, C. (2021). The genetic architecture of structural left–right asymmetry of the human brain. Nature Human Behaviour, 5, 1226-1236. doi:10.1038/s41562-021-01069-w.

    Abstract

    Left–right hemispheric asymmetry is an important aspect of healthy brain organization for many functions including language, and it can be altered in cognitive and psychiatric disorders. No mechanism has yet been identified for establishing the human brain’s left–right axis. We performed multivariate genome-wide association scanning of cortical regional surface area and thickness asymmetries, and subcortical volume asymmetries, using data from 32,256 participants from the UK Biobank. There were 21 significant loci associated with different aspects of brain asymmetry, with functional enrichment involving microtubule-related genes and embryonic brain expression. These findings are consistent with a known role of the cytoskeleton in left–right axis determination in other organs of invertebrates and frogs. Genetic variants associated with brain asymmetry overlapped with those associated with autism, educational attainment and schizophrenia. Comparably large datasets will likely be required in future studies, to replicate and further clarify the associations of microtubule-related genes with variation in brain asymmetry, behavioural and psychiatric traits.
  • Zhong, S., Wei, L., Zhao, C., Yang, L., Di, Z., Francks, C., & Gong, G. (2021). Interhemispheric relationship of genetic influence on human brain connectivity. Cerebral Cortex, 31(1), 77-88. doi:10.1093/cercor/bhaa207.

    Abstract

    To understand the origins of interhemispheric differences and commonalities/coupling in human brain wiring, it is crucial to determine how homologous interregional connectivities of the left and right hemispheres are genetically determined and related. To address this, in the present study, we analyzed human twin and pedigree samples with high-quality diffusion magnetic resonance imaging tractography and estimated the heritability and genetic correlation of homologous left and right white matter (WM) connections. The results showed that the heritability of WM connectivity was similar and coupled between the 2 hemispheres and that the degree of overlap in genetic factors underlying homologous WM connectivity (i.e., interhemispheric genetic correlation) varied substantially across the human brain: from complete overlap to complete nonoverlap. Particularly, the heritability was significantly stronger and the chance of interhemispheric complete overlap in genetic factors was higher in subcortical WM connections than in cortical WM connections. In addition, the heritability and interhemispheric genetic correlations were stronger for long-range connections than for short-range connections. These findings highlight the determinants of the genetics underlying WM connectivity and its interhemispheric relationships, and provide insight into genetic basis of WM connectivity asymmetries in both healthy and disease states.

    Additional information

    Supplementary data
  • 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.
  • 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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