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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.

      Key Words

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      Linked Article

      • Common or Rare Variants for Complex Traits?
        Biological PsychiatryVol. 75Issue 10
        • Preview
          Vrieze et al. (1) report a failure to identify any rare genetic variants associated with addiction-related phenotypes, using a rare variant genotyping chip in a sample of over 7000 individuals nested within over 2000 pedigrees. While sequencing costs remain high, the use of rare variant chips may be a cost-effective approach, given the large samples that will be required to identify these variants. However, it is worth considering what we can expect to learn from these efforts and what we have already learned.
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