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A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder
Journal article   Open access   Peer reviewed

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

Christina Corsello, Marc Coutanche, Geraldine Dawson, Maretha De Jonge, Richard Delorme, Eftichia Duketis, Fred Duque, Annette Estes, Penny Farrar, Bridget A Fernandez, …
Human genetics, Vol.131(4), pp.565-579
04/02/2012
DOI: 10.1007/s00439-011-1094-6
PMID: 21996756
url
https://doi.org/10.1007/s00439-011-1094-6View
Published (Version of record) Open Access

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.
 Life Sciences Haplotypes Genetic Predisposition to Disease Genome-Wide Association Study Humans Middle Aged Neurons and Cognition Nuclear Family Male Genotype Linkage Disequilibrium DNA Copy Number Variations Homozygote Adult Female Polymorphism, Single Nucleotide Child Development Disorders, Pervasive Child Cluster Analysis Cohort Studies

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