A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder
Year: 2011
Type: article
Study design: Observational Study
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.
Source: Human Genetics
Authors: Jillian P. Casey, Tiago Magalhaes, 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 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 Vicente, Sean Ennis
Institutions: University College Dublin, University of Lisbon, National Institute of Health Dr. Ricardo Jorge, Instituto Gulbenkian de Ciência, Trinity College Dublin, University of California, Los Angeles, Unidade Local de Saúde de Coimbra, University of Bologna, University of British Columbia, Guy's Hospital, Newcastle University, Centre National de la Recherche Scientifique, Institut Pasteur, Gènes, synapses et cognition, Université Paris Diderot, University of Illinois Chicago, University of Michigan, Warneford Hospital, University of Oxford, Autism Speaks, University of North Carolina at Chapel Hill, University Medical Center Utrecht, Inserm, Fondation FondaMental, Hôpital Robert-Debré, Goethe University Frankfurt, University of Washington, Centre for Human Genetics, Memorial University of Newfoundland, University of Miami, McGill University, University of Gothenburg, Children's Hospital of Philadelphia, University of Manchester, University of Pennsylvania, German Cancer Research Center, Icahn School of Medicine at Mount Sinai, Assistance Publique – Hôpitaux de Paris, Nathan Kline Institute for Psychiatric Research, New York University, Vanderbilt University, Université Toulouse - Jean Jaurès, Hospital for Sick Children, Centre for Applied Genomics, Indiana University School of Medicine, University of Utah, National and Kapodistrian University of Athens, Children's Hospital Agia Sophia, McMaster University, Centre for Addiction and Mental Health, University of Toronto, Yale University, University of Iowa, University of Birmingham, University of Alberta, Université Pierre-et-Marie-Curie, Stanford Medicine, Stanford University, Battelle, Abigail Wexner Research Institute, The Ohio State University
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,690
Funders: Autism Speaks, Canadian Institute for Advanced Research, Ontario Innovation Trust, Genome Canada, Wellcome Trust, Health Research Board, Ontario Genomics, National Children's Research Centre, Hussman Foundation, Fondation FondaMental, Fondation Orange, Ontario Genomics Institute, Sick Kids Foundation, National Institute for Health and Care Research, Irish Research Council for Science, Engineering and Technology, Deutsche Forschungsgemeinschaft, Institut National de la Santé et de la Recherche Médicale, Irish Research Council, Ministero della Salute, University of Toronto, Fondation de France, Hospital for Sick Children, National Institutes of Health, Canadian Institutes of Health Research, Medical Research Council, Ontario Ministry of Research and Innovation, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1196746099, Genetic analysis of 15q11-q13 in Autism, ACE: Translational Studies of Insistence on Sameness in Autism, UW Autism Center of Excellence, Genetic Studies in Neurological Disorders, Center for Genomic and Phenomic Studies in Autism, MOLECULAR GENETICS OF AUTISM, Identification and functional analysis of susceptibility genes in multifactorial disease., Greater New York Autism Research Center of Excellence, G4303903696, Molecular and Genetic Epidemiology of Autism, Genetics Association in Schizophrenia and Other Disorders, Unraveling the Genetic Etiology of Autism, NIHR Senior Investigator Award, RUPP-PI, G5409490729, G564567861, NEUROBIOLOGY AND GENETICS OF AUTISM, G6132732, G6232008589, Genetic association in schizophrenia and other disorders, A Comprehensive Approach to Identification of Autism Susceptibility Genes, INFRASTRUCTURE TO FACILITATE DISCOVERY OF AUTISM GENES, Heterogeneity in Autism Spectrum Disorders: Biological Mechanisms, Trajectories, and Treatment Response, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., COLLABORATIVE LINKAGE STUDY OF AUTISM, Postdoctoral Program in Functional Neurogenomics, G98478226
OpenAlex ID: W2067513312