Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Am J Epidemiol. 2019 Jun 1;188(6):1033-1054. doi: 10.1093/aje/kwz005.

Abstract

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

Keywords: alcohol consumption; cholesterol; gene-environment interactions; gene-lifestyle interactions; genome-wide association studies; lipids; triglycerides.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alcohol Drinking / epidemiology*
  • Cholesterol, HDL / blood
  • Cholesterol, LDL / blood
  • Continental Population Groups
  • Female
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Life Style
  • Lipids / blood*
  • Male
  • Middle Aged
  • Phenotype
  • Triglycerides / blood
  • Vascular Endothelial Growth Factor B
  • Young Adult

Substances

  • Cholesterol, HDL
  • Cholesterol, LDL
  • Lipids
  • Triglycerides
  • Vascular Endothelial Growth Factor B

Grant support