A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.

New CAR Research Sheds Light on

 

Universal Screening for Autism in Toddlers

TitleA novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
Publication TypeJournal Article
Year of Publication2012
AuthorsCasey, 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
JournalHum Genet
Volume131
Issue4
Pagination565-79
Date Published2012 Apr
ISSN1432-1203
KeywordsAdult, 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.

DOI10.1007/s00439-011-1094-6
Alternate JournalHum. Genet.
PubMed ID21996756
PubMed Central IDPMC3303079
Grant ListMH57881 / 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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