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

InterAct Consortium

doi:10.1093/aje/kwz005

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

InterAct Consortium

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	1033-1054
Number of pages	22
Journal	American Journal of Epidemiology
Volume	188
Issue number	6
DOIs	https://doi.org/10.1093/aje/kwz005
Publication status	Published - 1 Jun 2019

Bibliographical note

Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2019.

Keywords

Adolescent
Adult
Aged
Alcohol Drinking/epidemiology
Cholesterol, HDL/blood
Cholesterol, LDL/blood
Female
Genome-Wide Association Study
Genotype
Humans
Life Style
Lipids/blood
Male
Middle Aged
Phenotype
Racial Groups
Triglycerides/blood
Vascular Endothelial Growth Factor B
Young Adult

Access to Document

10.1093/aje/kwz005

Cite this

@article{9d37154f954a4d938f7dd1bccc49f5c7,

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 = "Adolescent, Adult, Aged, Alcohol Drinking/epidemiology, Cholesterol, HDL/blood, Cholesterol, LDL/blood, Female, Genome-Wide Association Study, Genotype, Humans, Life Style, Lipids/blood, Male, Middle Aged, Phenotype, Racial Groups, Triglycerides/blood, Vascular Endothelial Growth Factor B, Young Adult",

author = "{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 Ching-Yu Cheng 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 Fang-Chi Hsu and Jackson, {Anne U} and Muhammad Riaz and Saima Afaq and Zhe Wang and Wei Zhao",

note = "Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2019.",

year = "2019",

month = jun,

day = "1",

doi = "10.1093/aje/kwz005",

language = "English",

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 - 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 - Riaz, Muhammad

AU - Afaq, Saima

AU - Wang, Zhe

AU - Zhao, Wei

N1 - Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2019.

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 - Adolescent

KW - Adult

KW - Aged

KW - Alcohol Drinking/epidemiology

KW - Cholesterol, HDL/blood

KW - Cholesterol, LDL/blood

KW - Female

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Life Style

KW - Lipids/blood

KW - Male

KW - Middle Aged

KW - Phenotype

KW - Racial Groups

KW - Triglycerides/blood

KW - Vascular Endothelial Growth Factor B

KW - Young Adult

U2 - 10.1093/aje/kwz005

DO - 10.1093/aje/kwz005

M3 - Article

C2 - 30698716

SN - 0002-9262

VL - 188

SP - 1033

EP - 1054

JO - American Journal of Epidemiology

JF - American Journal of Epidemiology

IS - 6

ER -