Rare nonsynonymous exonic variants in addiction and behavioral disinhibition

Background Substance use is heritable, but few common genetic variants have been associated with these behaviors. Rare nonsynonymous exonic variants can now be efficiently genotyped, allowing exome-wide association tests. We identified and tested 111,592 nonsynonymous exonic variants for association with behavioral disinhibition and the use/misuse of nicotine, alcohol, and illicit drugs. Methods Comprehensive genotyping of exonic variation combined with single-variant and gene-based tests of association was conducted in 7181 individuals; 172 candidate addiction genes were evaluated in greater detail. We also evaluated the aggregate effects of nonsynonymous variants on these phenotypes using Genome-wide Complex Trait Analysis. Results No variant or gene was significantly associated with any phenotype. No association was found for any of the 172 candidate genes, even at reduced significance thresholds. All nonsynonymous variants jointly accounted for 35% of the heritability in illicit drug use and, when combined with common variants from a genome-wide array, accounted for 84% of the heritability. Conclusions Rare nonsynonymous variants may be important in etiology of illicit drug use, but detection of individual variants will require very large samples.