Title | A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Casey, JP, Magalhaes, T, Conroy, JM, Regan, R, Shah, N, Anney, R, Shields, DC, Abrahams, BS, Almeida, J, Bacchelli, E, Bailey, AJ, Baird, G, Battaglia, A, Berney, T, Bolshakova, N, Bolton, PF, Bourgeron, T, Brennan, S, Cali, P, Correia, C, Corsello, C, Coutanche, M, Dawson, G, de Jonge, M, Delorme, R, Duketis, E, Duque, F, Estes, A, Farrar, P, Fernandez, BA, Folstein, SE, Foley, S, Fombonne, E, Freitag, CM, Gilbert, J, Gillberg, C, Glessner, JT, Green, J, Guter, SJ, Hakonarson, H, Holt, R, Hughes, G, Hus, V, Igliozzi, R, Kim, C, Klauck, SM, Kolevzon, A, Lamb, JA, Leboyer, M, Le Couteur, A, Leventhal, BL, Lord, C, Lund, SC, Maestrini, E, Mantoulan, C, Marshall, CR, McConachie, H, McDougle, CJ, McGrath, J, McMahon, WM, Merikangas, A, Miller, J, Minopoli, F, Mirza, GK, Munson, J, Nelson, SF, Nygren, G, Oliveira, G, Pagnamenta, AT, Papanikolaou, K, Parr, JR, Parrini, B, Pickles, A, Pinto, D, Piven, J, Posey, DJ, Poustka, A, Poustka, F, Ragoussis, J, Rogé, B, Rutter, ML, Sequeira, AF, Soorya, L, Sousa, I, Sykes, N, Stoppioni, V, Tancredi, R, Tauber, M, Thompson, AP, Thomson, S, Tsiantis, J, van Engeland, H, Vincent, JB, Volkmar, F, Vorstman, JAS, Wallace, S, Wang, K, Wassink, TH, White, K, Wing, K, Wittemeyer, K, Yaspan, BL, Zwaigenbaum, L, Betancur, C, Buxbaum, JD, Cantor, RM, Cook, EH, Coon, H, Cuccaro, ML, Geschwind, DH, Haines, JL, Hallmayer, J, Monaco, AP, Nurnberger, JI, Pericak-Vance, MA, Schellenberg, GD, Scherer, SW, Sutcliffe, JS, Szatmari, P, Vieland, VJ, Wijsman, EM, Green, A, Gill, M, Gallagher, L, Vicente, A, Ennis, S |
Journal | Hum Genet |
Volume | 131 |
Issue | 4 |
Pagination | 565-79 |
Date Published | 2012 Apr |
ISSN | 1432-1203 |
Keywords | Adult, Child, Child Development Disorders, Pervasive, Cluster Analysis, Cohort Studies, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Haplotypes, Homozygote, Humans, Linkage Disequilibrium, Male, Middle Aged, Nuclear Family, Polymorphism, Single Nucleotide |
Abstract | Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data. |
DOI | 10.1007/s00439-011-1094-6 |
Alternate Journal | Hum. Genet. |
PubMed ID | 21996756 |
PubMed Central ID | PMC3303079 |
Grant List | MH57881 / MH / NIMH NIH HHS / United States P50 HD055782 / HD / NICHD NIH HHS / United States MH066673 / MH / NIMH NIH HHS / United States NS049261 / NS / NINDS NIH HHS / United States AS2482 / / Autism Speaks / United States MH55284 / MH / NIMH NIH HHS / United States MH080647 / MH / NIMH NIH HHS / United States MH061009 / MH / NIMH NIH HHS / United States HD055782 / HD / NICHD NIH HHS / United States MH081754 / MH / NIMH NIH HHS / United States T32 MH065215 / MH / NIMH NIH HHS / United States 1U24MH081810 / MH / NIMH NIH HHS / United States MH66766 / MH / NIMH NIH HHS / United States MH52708 / MH / NIMH NIH HHS / United States NS042165 / NS / NINDS NIH HHS / United States / / Canadian Institutes of Health Research / Canada 090532 / / Wellcome Trust / United Kingdom HD055784 / HD / NICHD NIH HHS / United States MH06359 / MH / NIMH NIH HHS / United States 075491/Z/04 / / Wellcome Trust / United Kingdom G0601030 / / Medical Research Council / United Kingdom NS026630 / NS / NINDS NIH HHS / United States HD35465 / HD / NICHD NIH HHS / United States HD055751 / HD / NICHD NIH HHS / United States |
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