Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use

Drug Alcohol Depend. 2018 Jul 1:188:94-101. doi: 10.1016/j.drugalcdep.2018.03.026. Epub 2018 Apr 25.

Abstract

Background: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use.

Methods: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N = 25,508) and "tobacco use disorder" (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses.

Results: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10-7) and rs8034191 (p = 6.31 × 10-7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use.

Discussion: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.

Keywords: Addiction; Alcohol; Exome; Nicotine; PRS; Pathway analysis; Rare variants; Tobacco.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking / epidemiology
  • Alcohol Drinking / genetics*
  • Alcoholism / diagnosis
  • Alcoholism / epidemiology
  • Alcoholism / genetics
  • Cohort Studies
  • Exons / genetics*
  • Female
  • Genetic Predisposition to Disease / epidemiology
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation / genetics*
  • Humans
  • Male
  • Nerve Tissue Proteins / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Receptors, Nicotinic / genetics
  • Risk Factors
  • Tobacco Use / epidemiology
  • Tobacco Use / genetics*
  • Tobacco Use Disorder / diagnosis
  • Tobacco Use Disorder / genetics

Substances

  • Nerve Tissue Proteins
  • Receptors, Nicotinic