A Genome-Wide Association Study of Autism Reveals a Common Novel Risk Locus at 5p14.1

Background: Autism is one of the most heritable neuropsychiatric disorders. However, its underlying genetic architecture has largely eluded description.

Objectives: To comprehensively examine the hypothesis that common variation is important in autism

Methods: We performed a genome-wide association study (GWAS) using a discovery dataset of 438 autistic Caucasian families genotyped on the Illumina Human 1M beadchip and validated the results using a publicly available GWAS dataset genotyped on 487 Caucasian autism families using the 550K Illumina beadchip.

Results: 96 single nucleotide polymorphisms (SNPs) demonstrated strong association with autism risk (p-value < 0.0001). 62 out of the top 96 SNPs were genotyped in the validation dataset. A novel region on chromosome 5p14.1 (25,830-26,100kb) appeared to be the only region being validated with a cluster of 3 SNPs (p [0.01, 0.04]). This encouraged us to have a closer investigation into this region. A further joint analysis of 46 SNPs genotyped on both datasets identified over 9 SNPs having more significant p-values (0.002 to 4.17E-6) than in either dataset alone. The examination in this region shows numerous sequence segments exhibiting a high degree of evolutionary conservation. In addition, there are three CNVs in proximity of the most significant SNPs. Although the immediate 1 Mb vicinity of the association region contains no known genes or candidates, flanking the region are CDH9 and CDH10, two genes that belong to the cadherin family, a group of proteins containing members that are involved in calcium-dependent cell-cell junctions in the nervous system and possible targets of regulatory action. The exhaustive molecular analysis is ongoing (see Griswold et al., this meeting).

Conclusions: Our findings demonstrate that in addition to multiple rare variations, part of the complex genetic architecture of autism involves common variation.