Hum Genet DOI 10.1007/s00439-011-1094-6 ORIGINAL INVESTIGATION A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder 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 • Ineˆs Sousa • Nuala Sykes • Vera Stoppioni • Raffaella Tancredi • Maı¨te´ 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 Jr. • 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 Received: 12 May 2011 / Accepted: 15 September 2011 Ó The Author(s) 2011. This article is published with open access at Springerlink.com Annemarie Poustka: deceased. Electronic supplementary material The online version of this article (doi:10.1007/s00439-011-1094-6) contains supplementary material, which is available to authorized users. J. P. Casey Á J. M. Conroy Á R. Regan Á N. Shah Á T. Magalhaes Á C. Correia Á A. F. Sequeira Á A. Vicente D. C. Shields Á A. Green Á S. Ennis Instituto Gulbenkian de Cıˆencia, Rua Quinta Grande, School of Medicine and Medical Science University College, 2780-156 Oeiras, Portugal Dublin 4, Ireland R. Anney Á N. Bolshakova Á S. Brennan Á G. Hughes Á T. Magalhaes Á C. Correia Á A. F. Sequeira Á A. Vicente J. McGrath Á A. Merikangas Á M. Gill Á L. Gallagher Instituto Nacional de Saude Dr Ricardo Jorge, Av Padre Cruz Autism Genetics Group, Department of Psychiatry, 1649-016, Lisbon, Portugal School of Medicine, Trinity College, Dublin 8, Ireland T. Magalhaes Á C. Correia Á A. F. Sequeira Á A. Vicente B. S. Abrahams Á D. H. Geschwind BioFIG, Center for Biodiversity, Functional and Integrative Department of Neurology, Center for Autism Research and Genomics, Campus da FCUL, C2.2.12, Campo Grande, Treatment, Program in Neurogenetics, Semel Institute, David 1749-016 Lisbon, Portugal Geffen School of Medicine at UCLA, Los Angeles, USA 123 Hum Genet to detect homozygous segments of identical haplotype Abstract Autism spectrum disorder (ASD) is a highly structure that are shared at a higher frequency amongst heritable disorder of complex and heterogeneous aetiology. ASD patients compared to parental controls. The analysis It is primarily characterized by altered cognitive ability was performed on 1,402 Autism Genome Project trios including impaired language and communication skills and genotyped for 1 million single nucleotide polymorphisms fundamental deficits in social reciprocity. Despite some (SNPs). We identified 25 known and 1,218 novel ASD notable successes in neuropsychiatric genetics, overall, the candidate genes in the discovery analysis including high heritability of ASD (*90%) remains poorly explained CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, by common genetic risk variants. However, recent studies EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. suggest that rare genomic variation, in particular copy Furthermore, 10 of the previously reported ASD genes and number variation, may account for a significant proportion 300 of the novel candidates identified in the discovery of the genetic basis of ASD. We present a large scale analysis were replicated in an independent sample of 1,182 analysis to identify candidate genes which may contain trios. Our results demonstrate that regions of HH are sig- low-frequency recessive variation contributing to ASD nificantly enriched for previously reported ASD candidate while taking into account the potential contribution of genes and the observed association is independent of population differences to the genetic heterogeneity of ASD. gene size (odds ratio 2.10). Our findings highlight the Our strategy, homozygous haplotype (HH) mapping, aims J. Almeida Á F. Duque Á G. Oliveira M. Coutanche Á S. Foley Á S. Wallace Á K. White Hospital Pedia´trico de Coimbra, 3000–076 Coimbra, Department of Psychiatry, University of Oxford, Portugal Warneford Hospital, Headington, Oxford OX3 7JX, UK E. Bacchelli Á E. Maestrini Á F. Minopoli G. Dawson Department of Biology, University of Bologna, Autism Speaks, New York 10016, USA 40126 Bologna, Italy G. Dawson A. J. Bailey Department of Psychiatry, University of North Carolina, Department of Psychiatry, University of British Columbia, Chapel Hill, NC 27599-3366, USA Vancouver V6T 2A1, Canada M. de Jonge Á H. Van Engeland Á J. A. S. Vorstman G. Baird Department of Child and Adolescent Psychiatry, Newcomen Centre, Guy’s Hospital, London SE1 9RT, UK University Medical Center, 3508 Utrecht, GA, The Netherlands A. Battaglia Á R. Igliozzi Á B. Parrini Á R. Tancredi Stella Maris Institute for Child and Adolescent Neuropsychiatry, R. Delorme 56128 Calambrone, Pisa, Italy INSERM U 955, Fondation FondaMental, APHP, Hoˆpital Robert Debre´, Child and Adolescent Psychiatry, T. Berney Á A. Le Couteur Á H. McConachie Á J. R. Parr 75019 Paris, France Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK E. Duketis Á C. M. Freitag Á F. Poustka Department of Child and Adolescent Psychiatry, T. Berney Á A. Le Couteur Á H. McConachie Á J. R. Parr Psychosomatics and Psychotherapy, Institute of Health and Society, Newcastle University, J.W. Goethe University Frankfurt, 60528 Frankfurt, Germany Newcastle Upon Tyne NE1 7RU, UK A. Estes P. F. Bolton Department of Speech and Hearing Sciences, Department of Child and Adolescent Psychiatry, University of Washington, Seattle, WA 98195, USA Institute of Psychiatry, London SE5 8AF, UK P. Farrar Á R. Holt Á G. K. Mirza Á A. T. Pagnamenta Á T. Bourgeron J. Ragoussis Á I. Sousa Á N. Sykes Á K. Wing Á A. P. Monaco Department of Human Genetics and Cognitive Functions, Wellcome Trust Centre for Human Genetics, Institut Pasteur, University Paris Diderot-Paris 7, University of Oxford, Oxford OX3 7BN, UK CNRS URA 2182, Fondation FondaMental, 75015 Paris, France B. A. Fernandez P. Cali Á S. J. Guter Á E. H. Cook Disciplines of Genetics and Medicine, Memorial University Department of Psychiatry, Institute for Juvenile Research, of Newfoundland, St John’s Newfoundland A1B 3V6, University of Illinois at Chicago, Chicago, IL 60612, USA Canada C. Corsello Á V. Hus Á C. Lord S. E. Folstein Autism and Communicative Disorders Centre, Department of Psychiatry, University of Miami School University of Michigan, Ann Arbor, MI 48109-2054, USA of Medicine, Miami, FL 33136, USA 123 Hum Genet applicability of HH mapping in complex disorders such as mutation (Durand et al. 2007; Lesch et al. 2008; Wong ASD and offer an alternative approach to the analysis of et al. 2002). Therefore, a rare pathogenic variant and sur- genome-wide association data. rounding haplotype is often enriched in frequency in a group of affected individuals compared with the haplotype frequency in a cohort of unaffected controls (The Interna- Introduction tional HapMap Consortium 2003). We propose that homozygous haplotypes (HH) that are shared by multiple Extended runs of homozygosity (ROH) have recently been affected individuals may be important for the discovery of highlighted as a genomic feature that may be useful to map recessive disease genes in complex disorders. We have recessive disease genes in outbred populations (Hilde- extended the traditional homozygosity mapping method by brandt et al. 2009; Lencz et al. 2007; Yang et al. 2010). analysing the haplotype within shared ROH regions to Furthermore, even in complex disorders, we expect to find identify homozygous segments of identical haplotype that an unusually high number of affected individuals to have are present uniquely or at a higher frequency in ASD the same haplotype in the region surrounding a disease probands compared to parental controls (Fig. 1).