Genome-Wide Association Study For Autism

Autism is a severe neurodevelopmental disorder with high clinical and genetic heterogeneity. The prevalence of autism is rising dramaticly. The most recent epidemiology study from American govement indicates that evey1in50children affected by autism. In China, there are0.6-1.8millions autism children estimated by WHO, and even1.5-7.8millions estimated by other scientists. Both genetic and environmental factors are involved in the etiology of autism, and the heritability is estimated upto90%. It has been revealed that chromosomal abnormablility, de novo and rare CNVs and SNVs are involved in autism genetic etiology, and several genes have been identified. However, all these idenfied variants can only explain a really small proportion of autism cases, the the genetic etiology for autism is mostly unclear.It has been hypothesized that multiple common variants accumulating or interating with environmental factors trigger the phenotypes of autism. Compared to rare and de novo variants studies, common variants identified associated with autism are very few. Here, we performed a genome-wide association study for autism from Chinese population. We recruited two cohorts from Chinese population, one of them is case-parents triads cohort and the other is case-control cohort. We combined genome-wide association study results from the two Chinese cohorts and replicated in three European ancestry cohorts. Meta-analysis was subsequently performed with the five cohorts. We further performed expression quatitative trait locus analysis and differential gene expression analysis for the identified variants or genes. Meta-analysis identified three single nucleotide polymorphisms (rs936938:p=4.49×10-8;rs6537835:p=3.26×10-8; rs1877455:p=8.70×10-8) and related haplotypes at AMPD1-NRAS-CSDE1(rs926938|rs8453|rsl0489525), TRIM33(rs6537825|rs11582563|rs11585926|rs11589568|rs7511633|rs6661053|rs11102800|rs3827735|rs11102807) and TRIM33-BCAS2(|rs10858047|rs11587400|rs1877455) associated with autism; and all mapped to a previous recurrent reported linkage region (1p13.2) with autism. These genetic associations are further supported by cis-acting regulatory effect on the gene expressions of CSDE1, NRAS and TRIM33and by differential expression of NRAS, CSDE1, BCAS2and TRIM33in the human prefrontal cortex of the postmortem brains between subjects with and without autism.Our study revealed three common haplotyps and related varaints associated with autism risk. The variants in the three hapltoypes may participate in the autism risk by regulating the mRNA expression level. Our study suggests that TRIM33and NRAS-CSDE1as candidate genes for autism, and may provide a novel insight into the etiology of autism.