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

InterAct Consortium & LifeLines Cohort Study Grp, Jun-2019, In : American Journal of Epidemiology. 188, 6, p. 1033-1054 22 p.

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  • InterAct Consortium
  • LifeLines Cohort Study Grp

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 x 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 x 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.

Original languageEnglish
Pages (from-to)1033-1054
Number of pages22
JournalAmerican Journal of Epidemiology
Volume188
Issue number6
Early online date29-Jan-2019
Publication statusPublished - Jun-2019

    Keywords

  • alcohol consumption, cholesterol, gene-environment interactions, gene-lifestyle interactions, genome-wide association studies, lipids, triglycerides, DENSITY-LIPOPROTEIN CHOLESTEROL, CORONARY-HEART-DISEASE, HDL CHOLESTEROL, LOW-FREQUENCY, BLOOD-LIPIDS, VEGF-B, METAANALYSIS, PLASMA, CONSUMPTION, INDIVIDUALS

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