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

2011; Springer Science+Business Media; Volume: 131; Issue: 4 Linguagem: Inglês

10.1007/s00439-011-1094-6

1432-1203

Jillian P. Casey, Tiago R. Magalhães, Judith Conroy, Regina Regan, Naisha Shah, Richard Anney, Denis C. Shields, Brett S. Abrahams, Joana Almeida, Elena Bacchelli, Anthony Bailey, Gillian Baird, Agatino Battaglia, T. P. Berney, Nadia Bolshakova, Patrick Bolton, Thomas Bourgeron, S. Brennan, Phil Cali, Catarina Correia, Christina Corsello, Marc N. Coutanche, Géraldine Dawson, Maretha Jonge, Richard Delorme, Eftichia Duketis, Frederico Duque, Annette Estes, Penny Farrar, Bridget A. Fernandez, Susan E. Folstein, S. Foley, Éric Fombonne, Christine M. Freitag, John R. Gilbert, Christopher Gillberg, Joseph Glessner, Jonathan Green, Stephen J. Guter, Hákon Hákonarson, Richard Holt, Gillian Hughes, Vanessa Hus, Roberta Igliozzi, Cecilia Kim, Sabine M. Klauck, Alexander Kolevzon, Janine A. Lamb, Marion Leboyer, Ann Le Couteur, Bennett Leventhal, Catherine Lord, Sabata C. Lund, Elena Maestrini, Carine Mantoulan, Christian R. Marshall, Helen McConachie, Christopher J. McDougle, Jane McGrath, William M. McMahon, Alison Merikangas, Judith Miller, Fiorella Minopoli, Ghazala Mirza, Jeff Munson, Stanley F. Nelson, Gudrun Nygren, Guiomar Oliveira, Alistair T. Pagnamenta, Katerina Papanikolaou, Jeremy Parr, Barbara Parrini, Andrew Pickles, Dalila Pinto, Joseph Piven, David J. Posey, Annemarie Poustka, Fritz Poustka, Jiannis Ragoussis, Bernadette Rogé, Michael Rutter, Ana Filipa Sequeira, Latha Soorya, Inês Sousa, Nuala Sykes, Vera Stoppioni, Raffaella Tancredi, M. Tauber, Ann Thompson, Susanne Thomson, John Tsiantis, Herman Van Engeland, John B. Vincent, Fred Volkmar, Jacob Vorstman, Simon Wallace, Kai Wang, Thomas H. Wassink, Kathy White, Kirsty Wing, Kerstin Wittemeyer, Brian L. Yaspan, Lonnie Zwaigenbaum, Catalina Betancur, Joseph D. Buxbaum, Rita M. Cantor, Edwin H. Cook, Hilary Coon, Michael L. Cuccaro, Daniel H. Geschwind, Jonathan L. Haines, Joachim Hallmayer, Anthony P. Monaco, John I. Nürnberger, Margaret A. Pericak‐Vance, Gerard D. Schellenberg, Stephen W. Scherer, James S. Sutcliffe, Peter Szatmari, Veronica J. Vieland, Ellen M. Wijsman, Andrew Green, Michael Gill, Louise Gallagher, Astrid M. Vicente, Sean Ennis,

Genomic variations and chromosomal abnormalities

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.