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

Jillian P Casey; Tiago Magalhaes; Judith Conroy; Regina Regan; Naisha Shah; Ann Anney; Denis C Shields; Brett S Abrahams; Joana Almeida; Elena Bacchelli; Anthony J Bailey; Gillian Gill; 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; Fred Duque; Ann Estes; Penny Farrar; Bridget A Fernandez; Susan E Folstein; Suzanne Foley; Eric Fombonne; Christine M Freitag; John Gilbert; Christopher Gill; Joseph Glessner; Jonathan Green; Stephen J Guter; Hakon Hakonarson; Richard Holt; 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 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 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

doi:10.1007/s00439-011-1094-6

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

Journal article

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

Jillian P Casey, Tiago Magalhaes, Judith Conroy, Regina Regan, Naisha Shah, Ann Anney, Denis C Shields, Brett S Abrahams, Joana Almeida, Elena Bacchelli, …

Human Genetics, Vol.131(4), pp.565-79

02/04/2012

DOI: https://doi.org/10.1007/s00439-011-1094-6

PMCID: PMC3303079

PMID: 21996756

Abstract

Adult

Child

Haplotypes

Homozygote

Humans

Linkage Disequilibrium

Male

Middle Aged

Nuclear Family

Polymorphism, Single Nucleotide

Child Development Disorders, Pervasive

Cluster Analysis

Cohort Studies

DNA Copy Number Variations

Female

Genetic Predisposition to Disease

Genome-Wide Association Study

Genotype

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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Title: A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
Creators - without role: Jillian P Casey - University College Dublin
Tiago Magalhaes - National Institute of Health Dr. Ricardo Jorge
Judith Conroy - University College Dublin
Regina Regan - University College Dublin
Naisha Shah - University College Dublin
Ann Anney
Denis C Shields - University College Dublin
Brett S Abrahams - Center for Autism and Related Disorders
Joana Almeida
Elena Bacchelli - University of Bologna
Anthony J Bailey - University of British Columbia
Gillian Gill - Open University of Israel
Agatino Battaglia - Fondazione Stella Maris
Tom Berney - Newcastle University
Nadia Bolshakova - Trinity College Dublin
Patrick F Bolton - Psychiatry Research Trust
Thomas Bourgeron - Institut Pasteur
Sean Brennan - Trinity College Dublin
Phil Cali - University of Illinois Chicago
Catarina Correia - Instituto Gulbenkian de Ciência
Christina Corsello - University of Michigan–Ann Arbor
Marc Coutanche - Warneford Hospital
Geraldine Dawson - Autism Speaks
Maretha de Jonge
Richard Delorme - Inserm
Eftichia Duketis - Goethe University Frankfurt
Fred Duque
Ann Estes
Penny Farrar - Centre for Human Genetics
Bridget A Fernandez - Memorial University of Newfoundland
Susan E Folstein - University of Miami
Suzanne Foley - Warneford Hospital
Eric Fombonne - McGill University
Christine M Freitag - Goethe University Frankfurt
John Gilbert - University of Miami
Christopher Gill
Joseph Glessner - Children's Hospital of Philadelphia
Jonathan Green - Johns Hopkins University
Stephen J Guter - University of Illinois Chicago
Hakon Hakonarson - Children's Hospital of Philadelphia
Richard Holt - Centre for Human Genetics
Vanessa Hus - University of Michigan–Ann Arbor
Roberta Igliozzi - Fondazione Stella Maris
Cecilia Kim - Children's Hospital of Philadelphia
Sabine M Klauck - German Cancer Research Center
Alexander Kolevzon
Janine A Lamb - University of Manchester
Marion Leboyer - Inserm
Ann Le Couteur - Newcastle University
Bennett L Leventhal - Nathan Kline Institute for Psychiatric Research
Catherine Lord - University of Michigan–Ann Arbor
Sabata C Lund - Vanderbilt University
Elena Maestrini - University of Bologna
Carine Mantoulan
Christian R Marshall - Hospital for Sick Children
Helen Mcconachie - Newcastle University
Christopher J Mcdougle - Indiana University – Purdue University Indianapolis
Jane Mcgrath - Trinity College Dublin
William M Mcmahon - University of Utah
Alison Merikangas - Trinity College Dublin
Judith Miller - University of Utah
Fiorella Minopoli - University of Bologna
Ghazala K Mirza - Centre for Human Genetics
Jeff Munson - University of Washington
Stanley F Nelson - University of California, Los Angeles
Gudrun Nygren - University of Gothenburg
Guiomar Oliveira - Sécurité et Qualité des Produits d'Origine Végétale
Alistair T Pagnamenta - University of Oxford
Katerina Papanikolaou - Children's Hospital Agia Sophia
Jeremy R Parr - Newcastle University
Barbara Parrini - Fondazione Stella Maris
Andrew Pickles - University of Manchester
Dalila Pinto - Hospital for Sick Children
Joseph Piven - University of North Carolina at Chapel Hill
David J Posey - Indiana University School of Medicine
Annemarie Poustka - German Cancer Research Center
Fritz Poustka - Goethe University Frankfurt
Jiannis Ragoussis - University of Oxford
Bernadette Roge
Michael Rutter - Psychiatry Research Trust
Ana F Sequeira - Instituto Gulbenkian de Ciência
Latha Soorya - Icahn School of Medicine at Mount Sinai
Inês Sousa - Centre for Human Genetics
Nuala Sykes - Centre for Human Genetics
Vera Stoppioni - Ospedale Santa Maria
Raffaella Tancredi - Fondazione Stella Maris
Maïté Tauber - Centre Hospitalier Universitaire de Toulouse
Ann P Thompson - McMaster University
Susanne Thomson - Vanderbilt University
John Tsiantis - Children's Hospital Agia Sophia
Herman van Engeland - University Medical Center Utrecht
John B Vincent - Centre for Addiction and Mental Health
Fred Volkmar - Yale University
Jacob a S Vorstman
Simon Wallace - University of Oxford
Kai Wang - Children's Hospital of Philadelphia
Thomas H Wassink - Carver Bible College
Kathy White - Warneford Hospital
Kirsty Wing - Centre for Human Genetics
Kerstin Wittemeyer - University of Birmingham
Brian L Yaspan - Vanderbilt University
Lonnie Zwaigenbaum - University of Alberta
Catalina Betancur - Inserm
Joseph D Buxbaum - Icahn School of Medicine at Mount Sinai
Rita M Cantor - University of California, Los Angeles
Edwin H Cook - University of Illinois Chicago
Hilary Coon - University of Utah
Michael Cuccaro - University of Miami
Daniel H. Geschwind - Center for Autism and Related Disorders
Jonathan L Haines - Université de Montpellier, Institut Charles Gerhardt Montpellier - ICGM
Joachim Hallmayer - Stanford University
Anthony P Monaco - University of Oxford
John I Nurnberger - Indiana University – Purdue University Indianapolis
Margaret A Pericak-Vance - University of Miami
Gerard D Schellenberg - University of Pennsylvania
Stephen W Scherer - Hospital for Sick Children
James S Sutcliffe - Vanderbilt University
Peter Szatmari - McMaster University
Veronica J Vieland - Battelle
Ellen M Wijsman - University of Washington
Andrew Green - University College Dublin
Michael Gill - Trinity College Dublin
Louise Gallagher - Trinity College Dublin
Astrid Vicente - Instituto Gulbenkian de Ciência
Sean Ennis - University College Dublin
Publication Details: Human Genetics, Vol.131(4), pp.565-79
Grant note: 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).
Identifiers: 9935024609311
Academic Unit: Institut Charles Gerhardt Montpellier - ICGM
Language: English
Resource Type: Journal article
Local Fields: hal-01548905