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.

Additional Metadata
Keywords alcohol consumption, cholesterol, gene-environment interactions, gene-lifestyle interactions, genome-wide association studies, lipids, triglycerides
Persistent URL dx.doi.org/10.1093/aje/kwz005, hdl.handle.net/1765/117281
Journal American Journal of Epidemiology
Grant This work was funded by the European Commission 7th Framework Programme; grant id h2020/692145 - Rise of scientific excellence and collaboration for implementing personalised medicine in Estonia (ePerMed), This work was funded by the European Commission 7th Framework Programme; grant id h2020/676550 - implementAtion anD OPeration of the gateway for healTh into BBMRI-ERIC (ADOPT BBMRI-ERIC), This work was funded by the European Commission 7th Framework Programme; grant id h2020/654248 - Coordinated Research Infrastructures Building Enduring Life-science services (CORBEL)
de Vries, P.S, Brown, M.R, Bentley, A.R, Sung, Y.J. (Yun J.), Winkler, T.W, Ntalla, I, … Morrison, A.C. (2019). Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. American Journal of Epidemiology, 188(6), 1033–1054. doi:10.1093/aje/kwz005