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

Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), InterAct Consortium

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1033-1054
Number of pages22
JournalAmerican journal of epidemiology
Volume188
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

Genome-Wide Association Study
Alcohols
Lipids
Vascular Endothelial Growth Factor B
Proprotein Convertases
Genome
Genes
Subtilisin
Lipid Metabolism
Alcohol Drinking
LDL Cholesterol
HDL Cholesterol
Theoretical Models
Demography

Keywords

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

ASJC Scopus subject areas

  • Epidemiology

Cite this

Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), & InterAct Consortium (2019). Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. American journal of epidemiology, 188(6), 1033-1054. https://doi.org/10.1093/aje/kwz005

Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. / Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study); InterAct Consortium.

In: American journal of epidemiology, Vol. 188, No. 6, 01.06.2019, p. 1033-1054.

Research output: Contribution to journalArticle

Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study) & InterAct Consortium 2019, 'Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions', American journal of epidemiology, vol. 188, no. 6, pp. 1033-1054. https://doi.org/10.1093/aje/kwz005
Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), InterAct Consortium. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. American journal of epidemiology. 2019 Jun 1;188(6):1033-1054. https://doi.org/10.1093/aje/kwz005
Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study) ; InterAct Consortium. / Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. In: American journal of epidemiology. 2019 ; Vol. 188, No. 6. pp. 1033-1054.
@article{32512cbc44d14361920ab9eb2be814bd,
title = "Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions",
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",
author = "{Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study)} and {InterAct Consortium} and {de Vries}, {Paul S.} and Brown, {Michael R.} and Bentley, {Amy R.} and Sung, {Yun J.} and Winkler, {Thomas W.} and Ioanna Ntalla and Karen Schwander and Kraja, {Aldi T.} and Xiuqing Guo and Nora Franceschini and Cheng, {Ching Yu} and Xueling Sim and Dina Vojinovic and Huffman, {Jennifer E.} and Musani, {Solomon K.} and Changwei Li and Feitosa, {Mary F.} and Richard, {Melissa A.} and Raymond Noordam and Hugues Aschard and Bartz, {Traci M.} and Bielak, {Lawrence F.} and Xuan Deng and Rajkumar Dorajoo and Lohman, {Kurt K.} and Manning, {Alisa K.} and Tuomo Rankinen and Smith, {Albert V.} and Tajuddin, {Salman M.} and Evangelos Evangelou and Mariaelisa Graff and Maris Alver and Mathilde Boissel and Chai, {Jin Fang} and Xu Chen and Jasmin Divers and Ilaria Gandin and Chuan Gao and Anuj Goel and Yanick Hagemeijer and Harris, {Sarah E.} and Hartwig, {Fernando P.} and Meian He and Horimoto, {Andrea R.V.R.} and Hsu, {Fang Chi} and Jackson, {Anne U.} and Anuradhani Kasturiratne and Lisa Yanek and Dan Arking and Becker, {Diane M}",
year = "2019",
month = "6",
day = "1",
doi = "10.1093/aje/kwz005",
language = "English (US)",
volume = "188",
pages = "1033--1054",
journal = "American Journal of Epidemiology",
issn = "0002-9262",
publisher = "Oxford University Press",
number = "6",

}

TY - JOUR

T1 - Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

AU - Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study)

AU - InterAct Consortium

AU - de Vries, Paul S.

AU - Brown, Michael R.

AU - Bentley, Amy R.

AU - Sung, Yun J.

AU - Winkler, Thomas W.

AU - Ntalla, Ioanna

AU - Schwander, Karen

AU - Kraja, Aldi T.

AU - Guo, Xiuqing

AU - Franceschini, Nora

AU - Cheng, Ching Yu

AU - Sim, Xueling

AU - Vojinovic, Dina

AU - Huffman, Jennifer E.

AU - Musani, Solomon K.

AU - Li, Changwei

AU - Feitosa, Mary F.

AU - Richard, Melissa A.

AU - Noordam, Raymond

AU - Aschard, Hugues

AU - Bartz, Traci M.

AU - Bielak, Lawrence F.

AU - Deng, Xuan

AU - Dorajoo, Rajkumar

AU - Lohman, Kurt K.

AU - Manning, Alisa K.

AU - Rankinen, Tuomo

AU - Smith, Albert V.

AU - Tajuddin, Salman M.

AU - Evangelou, Evangelos

AU - Graff, Mariaelisa

AU - Alver, Maris

AU - Boissel, Mathilde

AU - Chai, Jin Fang

AU - Chen, Xu

AU - Divers, Jasmin

AU - Gandin, Ilaria

AU - Gao, Chuan

AU - Goel, Anuj

AU - Hagemeijer, Yanick

AU - Harris, Sarah E.

AU - Hartwig, Fernando P.

AU - He, Meian

AU - Horimoto, Andrea R.V.R.

AU - Hsu, Fang Chi

AU - Jackson, Anne U.

AU - Kasturiratne, Anuradhani

AU - Yanek, Lisa

AU - Arking, Dan

AU - Becker, Diane M

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

AB - 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.

KW - alcohol consumption

KW - cholesterol

KW - gene-environment interactions

KW - gene-lifestyle interactions

KW - genome-wide association studies

KW - lipids

KW - triglycerides

UR - http://www.scopus.com/inward/record.url?scp=85067087923&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067087923&partnerID=8YFLogxK

U2 - 10.1093/aje/kwz005

DO - 10.1093/aje/kwz005

M3 - Article

C2 - 30698716

AN - SCOPUS:85067087923

VL - 188

SP - 1033

EP - 1054

JO - American Journal of Epidemiology

JF - American Journal of Epidemiology

SN - 0002-9262

IS - 6

ER -