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

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Title: A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder
Authors: Casey, Jillian
Magalhaes, Tiago
Conroy, Judith M.
Regan, Regina
Shah, Naisha
Shields, Denis C.
Green, Andrew
Ennis, Sean
et al.
Permanent link: http://hdl.handle.net/10197/6163
Date: Apr-2012
Online since: 2014-11-13T12:36:49Z
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.
Funding Details: Health Research Board
Type of material: Journal Article
Publisher: Springer
Journal: Human Genetics
Volume: 131
Issue: 4
Start page: 565
End page: 579
Copyright (published version): 2011 the Author
Keywords: Autism spectrum disorder (ASD)Genetics
DOI: 10.1007/s00439-011-1094-6
Language: en
Status of Item: Peer reviewed
Appears in Collections:Biomolecular and Biomedical Science Research Collection

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