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 1 Anthony J Bailey Gillian Gill 2 Agatino Battaglia 3 Tom Berney Nadia Bolshakova Patrick F Bolton Thomas Bourgeron 4, 5 Sean Brennan Phil Cali Catarina Correia Christina Corsello Marc Coutanche Geraldine Dawson Maretha De Jonge Richard Delorme 6 Eftichia Duketis 7 Fred Duque Ann Estes Penny Farrar Bridget A Fernandez 8 Susan E Folstein Suzanne Foley Eric Fombonne 9 Christine M Freitag 7 John Gilbert Christopher Gill Joseph Glessner Jonathan Green 10 Stephen J Guter Hakon Hakonarson Richard Holt 11 Vanessa Hus Roberta Igliozzi Cecilia Kim Sabine M Klauck 12 Alexander Kolevzon Janine A Lamb Marion Leboyer 13 Ann Le Couteur Bennett L Leventhal Catherine Lord Sabata C Lund Elena Maestrini 1 Carine Mantoulan Christian R Marshall 14, 15 Helen Mcconachie Christopher J Mcdougle Jane Mcgrath William M Mcmahon Alison Merikangas Judith Miller 16 Fiorella Minopoli Ghazala K Mirza Jeff Munson Stanley F Nelson Gudrun Nygren Guiomar Oliveira 17 Alistair T Pagnamenta Katerina Papanikolaou Jeremy R Parr Barbara Parrini Andrew Pickles Dalila Pinto 14 Joseph Piven David J Posey Annemarie Poustka Fritz Poustka 7 Jiannis Ragoussis Bernadette Roge Michael Rutter Ana F Sequeira Latha Soorya Inês Sousa Nuala Sykes Vera Stoppioni Raffaella Tancredi Maïté Tauber 18 Ann P Thompson 19 Susanne Thomson John Tsiantis Herman Van Engeland John B Vincent 20 Fred Volkmar Jacob a S Vorstman Simon Wallace Kai Wang Thomas H Wassink Kathy White 21 Kirsty Wing Kerstin Wittemeyer Brian L Yaspan Lonnie Zwaigenbaum 22 Catalina Betancur 23 Joseph D Buxbaum 24 Rita M Cantor Edwin H Cook Hilary Coon Michael Cuccaro Daniel H Geschwind Jonathan L Haines 25 Joachim Hallmayer Anthony P Monaco John I Nurnberger Margaret A Pericak-Vance Gerard D Schellenberg Stephen W Scherer 26 James S Sutcliffe Peter Szatmari 27 Veronica J Vieland Ellen M Wijsman Andrew Green Michael Gill Louise Gallagher Astrid Vicente Sean Ennis
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.
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Human Genetics, Springer Verlag, 2012, 131 (4), pp.565-79. 〈10.1007/s00439-011-1094-6〉
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Jillian P Casey, Tiago Magalhaes, Judith Conroy, Regina Regan, Naisha Shah, et al.. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.. Human Genetics, Springer Verlag, 2012, 131 (4), pp.565-79. 〈10.1007/s00439-011-1094-6〉. 〈hal-01548905〉



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