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

InterAct Consortium, LifeLines Cohort Study, Paul S. de Vries (Lead / Corresponding author), Michael R. Brown, Amy R. Bentley, Yun J. Sung, Thomas W. Winkler, Ioanna Ntalla, Karen Schwander, Aldi T. Kraja, Xiuqing Guo, Nora Franceschini, Ching-Yu Cheng, Xueling Sim, Dina Vojinovic, Jennifer E. Huffman, Solomon K. Musani, Changwei Li, Mary F. Feitosa, Melissa A. RichardRaymond Noordam, Hugues Aschard, Traci M. Bartz, Lawrence F. Bielak, Xuan Deng, Rajkumar Dorajoo, Kurt K. Lohman, Alisa K. Manning, Tuomo Rankinen, Albert V. Smith, Salman M. Tajuddin, Evangelos Evangelou, Mariaelisa Graff, Maris Alver, Mathilde Boissel, Jin Fang Chai, Xu Chen, Jasmin Divers, Ilaria Gandin, Chuan Gao, Anuj Goel, Yanick Hagemeijer, Sarah E. Harris, Fernando P. Hartwig, Meian He, Andrea R. V. R. Horimoto, Fang-Chi Hsu, Anne U. Jackson, Anuradhani Kasturiratne, Pirjo Komulainen, John M. Connell, Blair H. Smith, Dabeeru C. Rao (Lead / Corresponding author), Alanna C. Morrison

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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.

Original languageEnglish
Pages (from-to)1033-1054
Number of pages22
JournalAmerican Journal of Epidemiology
Issue number6
Early online date29 Jan 2019
Publication statusPublished - 1 Jun 2019


  • alcohol consumption
  • cholesterol
  • gene-environment interactions
  • gene-lifestyle interactions
  • genome-wide association studies
  • lipids
  • triglycerides

ASJC Scopus subject areas

  • Epidemiology


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