Multi-ancestry genome-wide association study of lipid levels incorporating gene-alcohol interactions

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Title: Multi-ancestry genome-wide association study of lipid levels incorporating gene-alcohol interactions
Authors: De Vries, PS
Brown, MR
Bentley, AR
Sung, YJ
Winkler, TW
Ntalla, I
Schwander, K
Kraja, AT
Guo, X
Franceschini, N
Cheng, C-Y
Tan, N
Taylor, KD
Teo, YY
Tham, YC
Uitterlinden, AG
Van Heemst, D
Vuckovic, D
Waldenberger, M
Wang, L
Aschard, H
Grabe, HJ
Wang, Y
Wang, Z
Wei, WB
Williams, C
Wilson, G
Wojczynski, MK
Yao, J
Yu, B
Yu, C
Yuan, J-M
Grove, ML
Bartz, TM
Zhao, W
Zonderman, AB
Becker, DM
Boehnke, M
Bowden, DW
Chambers, JC
Deary, IJ
Esko, T
Farrall, M
Gu, CC
Franks, PW
Bielak, LF
Freedman, BI
Froguel, P
Gasparini, P
Gieger, C
Horta, BL
Kamatani, Y
Kato, N
Kooner, JS
Harris, TB
Laakso, M
Leander, K
Deng, X
Lehtimäki, T
Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study)
Magnusson, PKE
Penninx, B
Pereira, AC
Rauramaa, R
Samani, NJ
Heikkinen, S
Scott, J
Shu, X-O
Van der Harst, P
Dorajoo, R
Wagenknecht, LE
Wang, YX
Wareham, NJ
Watkins, H
Weir, DR
Wickremasinghe, AR
Heng, C-K
Zheng, W
Elliott, P
North, KE
Bouchard, C
Lohman, KK
Evans, MK
Gudnason, V
Liu, C-T
Liu, Y
Psaty, BM
Hirata, M
Ridker, PM
Van Dam, RM
Kardia, SLR
Zhu, X
Rotimi, CN
Manning, AK
Mook-Kanamori, DO
Fornage, M
Kelly, TN
Fox, ER
Hixson, JE
Hayward, C
Van Duijn, CM
Tai, ES
Wong, TY
Liu, J
Rotter, JI
Rankinen, T
Gauderman, WJ
Province, MA
Munroe, PB
Howard, BV
Rice, K
Chasman, DI
Cupples, LA
Rao, DC
Morrison, AC
Smith, AV
Tajuddin, SM
Evangelou, E
Graff, M
Alver, M
Ikram, MA
Boissel, M
Chai, JF
Chen, X
Divers, J
Gandin, I
Gao, C
Goel, A
Hagemeijer, Y
Harris, SE
Hartwig, FP
Sim, X
He, M
Horimoto, ARVR
Hsu, F-C
Jackson, AU
Kasturiratne, A
Komulainen, P
Kühnel, B
Laguzzi, F
Lee, JH
Luan, J
InterAct Consortium
Lyytikäinen, L-P
Matoba, N
Nolte, IM
Pietzner, M
Riaz, M
Said, MA
Scott, RA
Sofer, T
Stancáková, A
Takeuchi, F
Jacobs, DR
Tayo, BO
Van der Most, PJ
Varga, TV
Wang, Y
Ware, EB
Wen, W
Yanek, LR
Zhang, W
Zhao, JH
Afaq, S
Johnson, C
Amin, N
Amini, M
Arking, DE
Aung, T
Ballantyne, C
Boerwinkle, E
Broeckel, U
Campbell, A
Canouil, M
Charumathi, S
Jonas, JB
Chen, Y-DI
Connell, JM
De Faire, U
De Las Fuentes, L
De Mutsert, R
De Silva, HJ
Ding, J
Dominiczak, AF
Duan, Q
Eaton, CB
Kammerer, CM
Eppinga, RN
Faul, JD
Fisher, V
Forrester, T
Franco, OH
Friedlander, Y
Ghanbari, M
Giulianini, F
Katsuya, T
Khor, CC
Kilpeläinen, TO
Koh, W-P
Koistinen, HA
Vojinovic, D
Kolcic, I
Kooperberg, C
Krieger, JE
Kritchevsky, SB
Kubo, M
Kuusisto, J
Lakka, TA
Langefeld, CD
Langenberg, C
Launer, LJ
Huffman, JE
Lehne, B
Lemaitre, RN
Li, Y
Liang, J
Liu, J
Liu, K
Loh, M
Louie, T
Mägi, R
Manichaikul, AW
Musani, SK
McKenzie, CA
Meitinger, T
Metspalu, A
Milaneschi, Y
Milani, L
Mohlke, KL
Mosley, TH
Mukamal, KJ
Nalls, MA
Nauck, M
Li, C
Nelson, CP
Sotoodehnia, N
O'Connell, JR
Palmer, ND
Pazoki, R
Pedersen, NL
Peters, A
Peyser, PA
Polasek, O
Poulter, N
Feitosa, MF
Raffel, LJ
Raitakari, OT
Reiner, AP
Rice, TK
Rich, SS
Robino, A
Robinson, JG
Rose, LM
Rudan, I
Schmidt, CO
Richard, MA
Schreiner, PJ
Scott, WR
Sever, P
Shi, Y
Sidney, S
Sims, M
Smith, BH
Smith, JA
Snieder, H
Starr, JM
Noordam, R
Strauch, K
Item Type: Journal Article
Abstract: 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.
Issue Date: Jun-2019
Date of Acceptance: 8-Jan-2019
ISSN: 1476-6256
Publisher: Oxford University Press (OUP)
Start Page: 1033
End Page: 1054
Journal / Book Title: American Journal of Epidemiology
Volume: 188
Issue: 6
Copyright Statement: © 2019 Oxford University Press. This is a pre-copy-editing, author-produced version of an article accepted for publication in American Journal of Epidemiology following peer review. The definitive publisher-authenticated version American Journal of Epidemiology, kwz005 is available online at:
Sponsor/Funder: Home Office
Action on Hearing Loss
Imperial College Healthcare NHS Trust- BRC Funding
British Heart Foundation
Medical Research Council (MRC)
Wellcome Trust
National Institute for Health Research
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
National Institute for Health Research
National Institute for Health Research
Funder's Grant Number: PG0484
Keywords: Science & Technology
Life Sciences & Biomedicine
Public, Environmental & Occupational Health
alcohol consumption
gene-environment interactions
gene-lifestyle interactions
genome-wide association studies
alcohol consumption
gene-environment interactions
gene-lifestyle interactions
genome-wide association studies
InterAct Consortium
Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study)
11 Medical and Health Sciences
01 Mathematical Sciences
Publication Status: Published
Conference Place: United States
Embargo Date: 2020-01-29
Article Number: kwz005
Online Publication Date: 2019-01-29
Appears in Collections:Clinical Sciences
National Heart and Lung Institute
Molecular Sciences
Faculty of Medicine
Epidemiology, Public Health and Primary Care

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