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

Research output: Contribution to journalJournal articlepeer-review

  • Paul S de Vries
  • 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 Richard
  • Raymond 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
  • Jing Hua Zhao
  • Oskari Kilpeläinen, Tuomas
  • InterAct Consortium
  • V Varga, Tibor

An individual'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 multi-ancestry 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 five ancestry groups. Genetic main and interaction effects were jointly assessed by 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 Stage 1 and Stage 2, 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 (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.

Original languageEnglish
JournalAmerican Journal of Epidemiology
Volume188
Issue number6
Pages (from-to)1033-1054
ISSN0002-9262
DOIs
Publication statusPublished - 2019

ID: 213240324