A Comprehensive Meta-Analysis of Common Genetic Variants in Autism Spectrum Conditions

Thursday, May 14, 2015: 5:30 PM-7:00 PM
Imperial Ballroom (Grand America Hotel)
V. Warrier1, V. Chee2, P. L. Smith3, B. Chakrabarti4 and S. Baron-Cohen5, (1)University of Cambridge, Cambridge, England, United Kingdom, (2)Autism Research Centre, Cambridge, United Kingdom, (3)Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom, (4)Centre for Integrative Neuroscience and Neurodynamics, School of Psychology and Clinical Language Sciences, University of Reading, Reading, United Kingdom, (5)Autism Research Centre, University of Cambridge, Cambridge, United Kingdom
Background:  Autism Spectrum Conditions (ASC) are a group of neurodevelopmental conditions characterized by difficulties in social interaction and communication alongside repetitive and stereotyped behaviours. ASC is heritable, and common genetic variants contribute to substantial phenotypic variability. More than 600 genes have been implicated in ASC to date. Nevertheless, a comprehensive investigation of candidate gene association studies in ASC is lacking.

Objectives:  To systematically review candidate gene association studies in ASC, and perform a meta-analyses of common genetic variants investigated in three or more independent cohorts. 

Methods: We systematically reviewed the literature for association studies for 553 genes associated with ASC. We identified 58 common genetic variants in 27 genes that have been investigated in three or more independent cohorts and conducted a meta-analysis for 55 of these variants. Additionally, we investigated publication bias and sensitivity, and performed stratified analyses based on ethnicity or study methodology for a subset of these variants. 

Results: We identified 16 variants nominally significant for the mean effect size, nine of which had P-values < 0.01. The top nine variants were located in seven genes: DRD3, CNTNAP2, EN2, RELN, OXTR, SLC25A12, and MTHFR. The most significant SNP was rs167771 in DRD3 (OR = 1.822, P-value = 9.08x10-6). The mean effect sizes for the variants investigated were modest and lay between 0.781 (0.446 - 1.368) for MAOA uVNTR and 1.822 (1.398-2.375) for DRD3 rs167771. In the stratified analyses, seven variants had P-values below 0.05. These seven variants were in five genes (EN2, OXTR, RELN, SLC6A4, and SLC25A12). Publication bias was significant for two variants in OXTR. Sensitivity was an issue for five of the variants investigated. Finally, heterogeneity in effect sizes was significant for a large fraction of the variants tested and was positively correlated with a number of independent datasets investigated per common variant.  We were able to remove some of the heterogeneity after stratifying for ethnicity and study methodology.  

Conclusions:  This is the first study to comprehensively examine common variants in candidate genes for ASC through meta-analysis. It supports the role of common genetic variation in the aetiology of ASC and prioritizes specific variants for further investigation.

See more of: Genetics
See more of: Genetics