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. 2014 May 15;75(10):783-9.
doi: 10.1016/j.biopsych.2013.08.027. Epub 2013 Oct 4.

Rare nonsynonymous exonic variants in addiction and behavioral disinhibition

Scott I Vrieze  1 , Shuang Feng  2 , Michael B Miller  3 , Brian M Hicks  4 , Nathan Pankratz  5 , Gonçalo R Abecasis  2 , William G Iacono  3 , Matt McGue  3
Affiliations

Rare nonsynonymous exonic variants in addiction and behavioral disinhibition

Scott I Vrieze et al. Biol Psychiatry. .

Abstract

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.

Keywords: Addiction; alcohol; behavioral disinhibition; drug; exome; nonsynonymous; tobacco.

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Conflict of interest statement

Financial Disclosures

All authors report no biomedical financial interests or potential conflicts of interest.

Comment in

  • Common or rare variants for complex traits?
    Munafò MR, Flint J. Munafò MR, et al. Biol Psychiatry. 2014 May 15;75(10):752-3. doi: 10.1016/j.biopsych.2014.03.010. Biol Psychiatry. 2014. PMID: 24780010 No abstract available.

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