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

source extracted confidence: high 2026-04-09
#alcohol-drinking #alcoholism #cohort-studies #exons #female

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

Marees et al., 2018 | Drug Alcohol Depend | Meta Analysis

Citation

Marees Andries T, Hammerschlag Anke R, ... Derks Eske M. Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use. Drug Alcohol Depend. 2018-Jul-01;188:94-101. doi:10.1016/j.drugalcdep.2018.03.026

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.

Key Findings

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.

Outcomes Measured

  • Requires manual extraction

Population

Field Value
Population See abstract
Sample Size 25508
Age Range See abstract
Condition See abstract

MeSH Terms

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

Evidence Classification

  • Level: Meta Analysis
  • Publication Types: Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't
  • Vertical: niacin

Provenance

Source extracted via PubMed E-utilities API on 2026-04-09