A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
2012
Casey, Jillian P | Magalhaes, Tiago | Conroy, Judith | Regan, Regina | Shah, Naisha | Anney, Ann | Shields, Denis C | Abrahams, Brett S | Almeida, Joana | Bacchelli, Elena | Bailey, Anthony J | Gill, Gillian | Battaglia, Agatino | Berney, Tom | Bolshakova, Nadia | Bolton, Patrick F | Bourgeron, Thomas | Brennan, Sean | Cali, Phil | Correia, Catarina | Corsello, Christina | Coutanche, Marc | Dawson, Geraldine | de Jonge, Maretha | Delorme, Richard | Duketis, Eftichia | Duque, Fred | Estes, Ann | Farrar, Penny | Fernandez, Bridget A | Folstein, Susan E | Foley, Suzanne | Fombonne, Eric | Freitag, Christine M | Gilbert, John | Gill, Christopher | Glessner, Joseph | Green, Jonathan | Guter, Stephen J | Hakonarson, Hakon | Holt, Richard | Hus, Vanessa | Igliozzi, Roberta | Kim, Cecilia | Klauck, Sabine M | Kolevzon, Alexander | Lamb, Janine A | Leboyer, Marion | Le Couteur, Ann | Leventhal, Bennett L | Lord, Catherine | Lund, Sabata C | Maestrini, Elena | Mantoulan, Carine | Marshall, Christian R | Mcconachie, Helen | Mcdougle, Christopher J | Mcgrath, Jane | Mcmahon, William M | Merikangas, Alison | Miller, Judith | Minopoli, Fiorella | Mirza, Ghazala K | Munson, Jeff | Nelson, Stanley F | Nygren, Gudrun | Oliveira, Guiomar | Pagnamenta, Alistair T | Papanikolaou, Katerina | Parr, Jeremy R | Parrini, Barbara | Pickles, Andrew | Pinto, Dalila | Piven, Joseph | Posey, David J | Poustka, Annemarie | Poustka, Fritz | Ragoussis, Jiannis | Roge, Bernadette | Rutter, Michael | Sequeira, Ana F | Soorya, Latha | Sousa, Inês | Sykes, Nuala | Stoppioni, Vera | Tancredi, Raffaella | Tauber, Maïté | Thompson, Ann P | Thomson, Susanne | Tsiantis, John | van Engeland, Herman | Vincent, John B | Volkmar, Fred | Vorstman, Jacob a S | Wallace, Simon | Wang, Kai | Wassink, Thomas H | White, Kathy | Wing, Kirsty | Wittemeyer, Kerstin | Yaspan, Brian L | Zwaigenbaum, Lonnie | Betancur, Catalina | Buxbaum, Joseph D | Cantor, Rita M | Cook, Edwin H | Coon, Hilary | Cuccaro, Michael | Geschwind, Daniel H. | Haines, Jonathan L | Hallmayer, Joachim | Monaco, Anthony P | Nurnberger, John I | Pericak-Vance, Margaret A | Schellenberg, Gerard D | Scherer, Stephen W | Sutcliffe, James S | Szatmari, Peter | Vieland, Veronica J | Wijsman, Ellen M | Green, Andrew | Gill, Michael | Gallagher, Louise | Vicente, Astrid | Ennis, Sean | Alma Mater Studiorum Università di Bologna = University of Bologna (UNIBO) | Open University of Israël | IRCCS Fondazione Stella Maris [Pisa] | Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)) ; Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS) | Institut Pasteur [Paris] (IP) | AP-HP Hôpital universitaire Robert-Debré [Paris] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP) | Goethe University Frankfurt = Goethe-Universität Frankfurt am Main | Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN) | McGill University = Université McGill [Montréal, Canada] | Johns Hopkins University (JHU) | Autism Research Centre and Section of Developmental Psychiatry ; University of Cambridge [UK] (CAM) | German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ) | Psychiatrie génétique ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Mondor de Recherche Biomédicale | The Hospital for sick children [Toronto] (SickKids) | University of Toronto | Australian Resources Research Centre, Kensington, | Sécurité et Qualité des Produits d'Origine Végétale (SQPOV) ; Avignon Université (AU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) | Centre Hospitalier Universitaire de Toulouse (CHU Toulouse) | School of Chemistry ; Dalhousie University [Halifax] | DLR Institut für Planetenforschung ; Deutsches Zentrum für Luft- und Raumfahrt [Berlin] (DLR) | Department of Human Genetics ; University of Chicago | University of Alberta | Génétique de l'autisme = Genetics of Autism (NPS-01) ; Neuroscience Paris Seine (NPS) ; Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS) ; Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS) ; Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) | Seaver Autism Center for Research and Treatment ; Icahn School of Medicine at Mount Sinai [New York] (MSSM) | Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM) ; Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS) | University of Koblenz-Landau | McMaster University [Hamilton, Ontario] | The authors acknowledge the families participating in the study and the main funders of the Autism Genome Project Consortium (AGP): Autism Speaks (USA), the Health Research Board (HRB; Ireland), The Medical Research Council (MRC; UK), Genome Canada/Ontario Genomics Institute, and the Hilibrand Foundation (USA). Additional support for individual groups was provided by the US National Institutes of Health (NIH grants HD055751, HD055782, HD055784, HD35465, MH52708, MH55284, MH57881, MH061009, MH06359, MH066673, MH080647, MH081754, MH66766, NS026630, NS042165, NS049261), the Canadian Institute for Advanced Research (CIFAR), the Canadian Institutes for Health Research (CIHR), Assistance Publique–Hôpitaux de Paris (France), Autistica, Canada Foundation for Innovation/Ontario Innovation Trust, Deutsche Forschungsgemeinschaft (grant Po 255/17-4) (Germany), EC Sixth FP AUTISM MOLGEN, Fundação Calouste Gulbenkian (Portugal), Fondation de France, Fondation FondaMental (France), Fondation Orange (France), Fondation pour la Recherche Médicale (France), Fundação para a Ciência e Tecnologia (Portugal), the Hospital for Sick Children Foundation and University of Toronto (Canada), INSERM (France), Institut Pasteur (France), the Italian Ministry of Health (convention 181 of 19.10.2001), the John P. Hussman Foundation (USA), McLaughlin Centre (Canada), Ontario Ministry of Research and Innovation (Canada), the Seaver Foundation (USA), the Swedish Science Council, The Centre for Applied Genomics (Canada), the Utah Autism Foundation (USA) and the Wellcome Trust core award 075491/Z/04 (UK). We acknowledge support from the Autism Genetic Resource Exchange (AGRE) and Autism Speaks. We gratefully acknowledge the resources provided by the AGRE consortium and the participating AGRE families. AGRE is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M. Lajonchere (PI). We wish to acknowledge the National Children’s Research Centre Our Lady’s Children’s Hospital Crumlin Ireland for providing additional support and the Wellcome Trust Case–Control Consortium for providing data sets that were used as part of this study. J.P.C is supported by an EMBARK postgraduate award from the Irish Research Council for Science, Engineering and Technology (IRCSET). | The AGRE Consortium
International audience
Afficher plus [+] Moins [-]anglais. 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.
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