Open Access

Jillian P. Casey, Tiago R. Magalhães, Judith M. Conroy, Regina Regan, Naisha Shah, Richard Anney, Denis C. Shields, Brett S. Abrahams, Joana Almeida, Elena Bacchelli, Anthony J. Bailey, Gillian Baird, Agatino Battaglia, Tom Berney, Nadia Bolshakova, Patrick F. Bolton, Thomas Bourgeron, Sean Brennan, Phil Cali, Catarina Correia, Christina Corsello, Marc Coutanche, Geraldine Dawson, Maretha de Jonge, Richard Delorme, Eftichia Duketis, Frederico Duque, Annette Estes, Penny Farrar, Bridget A. Fernandez, Susan E. Folstein, Suzanne Foley, Eric Fombonne, Christine M. Freitag, John Gilbert, Christopher Gillberg, Joseph T. Glessner, Jonathan Green, Stephen J. Guter, Hakon Hakonarson, Richard Holt, Gillian Hughes, Vanessa Hus, Roberta Igliozzi, Cecilia Kim, Sabine M. Klauck, Alexander Kolevzon, Janine A. Lamb, Marion Leboyer, Ann Le Couteur, Bennett L. 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 K. Mirza, Jeff Munson, Stanley F. Nelson, Gudrun Nygren, Guiomar Oliveira, Alistair T. Pagnamenta, Katerina Papanikolaou, Jeremy R. Parr, Barbara Parrini, Andrew Pickles, Dalila Pinto, Joseph Piven, David J. Posey, Annemarie Poustka, Fritz Poustka, Jiannis Ragoussis, Bernadette Roge, Michael L. Rutter, Ana F. Sequeira, Latha Soorya, Inês Sousa, Nuala Sykes, Vera Stoppioni, Raffaella Tancredi, Maïté Tauber, Ann P. Thompson, Susanne Thomson, John Tsiantis, Herman van Engeland, John B. Vincent, Fred Volkmar, Jacob A. S. 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. Nurnberger, Margaret Ann 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

• 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.