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 (US) |
|---|---|
| Pages (from-to) | 1033-1054 |
| Number of pages | 22 |
| Journal | American journal of epidemiology |
| Volume | 188 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 1 2019 |
Keywords
- Alcohol Consumption
- Cholesterol
- Gene-Environment Interactions
- Gene-Lifestyle Interactions
- Genome-Wide Association Studies
- Lipids
- Triglycerides
ASJC Scopus subject areas
- General Medicine
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In: American journal of epidemiology, Vol. 188, No. 6, 01.06.2019, p. 1033-1054.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
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 - Komulainen, Pirjo
AU - Kühnel, Brigitte
AU - Laguzzi, Federica
AU - Lee, Joseph H.
AU - Luan, Jian'An
AU - Lyytikäinen, Leo Pekka
AU - Matoba, Nana
AU - Nolte, Ilja M.
AU - Pietzner, Maik
AU - Riaz, Muhammad
AU - Said, M. Abdullah
AU - Scott, Robert A.
AU - Sofer, Tamar
AU - Stančáková, Alena
AU - Takeuchi, Fumihiko
AU - Tayo, Bamidele O.
AU - Van Der Most, Peter J.
AU - Varga, Tibor V.
AU - Wang, Yajuan
AU - Ware, Erin B.
AU - Wen, Wanqing
AU - Yanek, Lisa R.
AU - Zhang, Weihua
AU - Zhao, Jing Hua
AU - Afaq, Saima
AU - Amin, Najaf
AU - Amini, Marzyeh
AU - Arking, Dan E.
AU - Aung, Tin
AU - Ballantyne, Christie
AU - Boerwinkle, Eric
AU - Broeckel, Ulrich
AU - Campbell, Archie
AU - Canouil, Mickaël
AU - Charumathi, Sabanayagam
AU - Chen, Yii Der Ida
AU - Connell, John M.
AU - De Faire, Ulf
AU - De Las Fuentes, Lisa
AU - De Mutsert, Rene
AU - De Silva, H. Janaka
AU - Ding, Jingzhong
AU - Dominiczak, Anna F.
AU - Duan, Qing
AU - Eaton, Charles B.
AU - Eppinga, Ruben N.
AU - Faul, Jessica D.
AU - Fisher, Virginia
AU - Forrester, Terrence
AU - Franco, Oscar H.
AU - Friedlander, Yechiel
AU - Ghanbari, Mohsen
AU - Giulianini, Franco
AU - Grabe, Hans J.
AU - Grove, Megan L.
AU - Gu, C. Charles
AU - Harris, Tamara B.
AU - Heikkinen, Sami
AU - Heng, Chew Kiat
AU - Hirata, Makoto
AU - Hixson, James E.
AU - Howard, Barbara V.
AU - Ikram, M. Arfan
AU - Jacobs, David R.
AU - Johnson, Craig
AU - Jonas, Jost Bruno
AU - Kammerer, Candace M.
AU - Katsuya, Tomohiro
AU - Khor, Chiea Chuen
AU - Kilpeläinen, Tuomas O.
AU - Koh, Woon Puay
AU - Koistinen, Heikki A.
AU - Kolcic, Ivana
AU - Kooperberg, Charles
AU - Krieger, Jose E.
AU - Kritchevsky, Steve B.
AU - Kubo, Michiaki
AU - Kuusisto, Johanna
AU - Lakka, Timo A.
AU - Langefeld, Carl D.
AU - Langenberg, Claudia
AU - Launer, Lenore J.
AU - Lehne, Benjamin
AU - Lemaitre, Rozenn N.
AU - Li, Yize
AU - Liang, Jingjing
AU - Liu, Jianjun
AU - Liu, Kiang
AU - Loh, Marie
AU - Louie, Tin
AU - Mägi, Reedik
AU - Manichaikul, Ani W.
AU - McKenzie, Colin A.
AU - Meitinger, Thomas
AU - Metspalu, Andres
AU - Milaneschi, Yuri
AU - Milani, Lili
AU - Mohlke, Karen L.
AU - Mosley, Thomas H.
AU - Mukamal, Kenneth J.
AU - Nalls, Mike A.
AU - Nauck, Matthias
AU - Nelson, Christopher P.
AU - Sotoodehnia, Nona
AU - O'Connell, Jeff R.
AU - Palmer, Nicholette D.
AU - Pazoki, Raha
AU - Pedersen, Nancy L.
AU - Peters, Annette
AU - Peyser, Patricia A.
AU - Polasek, Ozren
AU - Poulter, Neil
AU - Raffel, Leslie J.
AU - Raitakari, Olli T.
AU - Reiner, Alex P.
AU - Rice, Treva K.
AU - Rich, Stephen S.
AU - Robino, Antonietta
AU - Robinson, Jennifer G.
AU - Rose, Lynda M.
AU - Rudan, Igor
AU - Schmidt, Carsten O.
AU - Schreiner, Pamela J.
AU - Scott, William R.
AU - Sever, Peter
AU - Shi, Yuan
AU - Sidney, Stephen
AU - Sims, Mario
AU - Smith, Blair H.
AU - Smith, Jennifer A.
AU - Snieder, Harold
AU - Starr, John M.
AU - Strauch, Konstantin
AU - Tan, Nicholas
AU - Taylor, Kent D.
AU - Teo, Yik Ying
AU - Tham, Yih Chung
AU - Uitterlinden, Andre G.
AU - Van Heemst, Diana
AU - Vuckovic, Dragana
AU - Waldenberger, Melanie
AU - Wang, Lihua
AU - Wang, Yujie
AU - Wang, Zhe
AU - Wei, Wen Bin
AU - Williams, Christine
AU - Wilson, Gregory
AU - Wojczynski, Mary K.
AU - Yao, Jie
AU - Yu, Bing
AU - Yu, Caizheng
AU - Yuan, Jian Min
AU - Zhao, Wei
AU - Zonderman, Alan B.
AU - Becker, Diane M.
AU - Boehnke, Michael
AU - Bowden, Donald W.
AU - Chambers, John C.
AU - Deary, Ian J.
AU - Esko, Tõnu
AU - Farrall, Martin
AU - Franks, Paul W.
AU - Freedman, Barry I.
AU - Froguel, Philippe
AU - Gasparini, Paolo
AU - Gieger, Christian
AU - Horta, Bernardo L.
AU - Kamatani, Yoichiro
AU - Kato, Norihiro
AU - Kooner, Jaspal S.
AU - Laakso, Markku
AU - Leander, Karin
AU - Lehtimäki, Terho
AU - Magnusson, Patrik K.E.
AU - Penninx, Brenda
AU - Pereira, Alexandre C.
AU - Rauramaa, Rainer
AU - Samani, Nilesh J.
AU - Scott, James
AU - Shu, Xiao Ou
AU - Van Der Harst, Pim
AU - Wagenknecht, Lynne E.
AU - Wang, Ya Xing
AU - Wareham, Nicholas J.
AU - Watkins, Hugh
AU - Weir, David R.
AU - Wickremasinghe, Ananda R.
AU - Zheng, Wei
AU - Elliott, Paul
AU - North, Kari E.
AU - Bouchard, Claude
AU - Evans, Michele K.
AU - Gudnason, Vilmundur
AU - Liu, Ching Ti
AU - Liu, Yongmei
AU - Psaty, Bruce M.
AU - Ridker, Paul M.
AU - Van Dam, Rob M.
AU - Kardia, Sharon L.R.
AU - Zhu, Xiaofeng
AU - Rotimi, Charles N.
AU - Mook-Kanamori, Dennis O.
AU - Fornage, Myriam
AU - Kelly, Tanika N.
AU - Fox, Ervin R.
AU - Hayward, Caroline
AU - Van Duijn, Cornelia M.
AU - Tai, E. Shyong
AU - Wong, Tien Yin
AU - Liu, Jingmin
AU - Rotter, Jerome I.
AU - Gauderman, W. James
AU - Province, Michael A.
AU - Munroe, Patricia B.
AU - Rice, Kenneth
AU - Chasman, Daniel I.
AU - Cupples, L. Adrienne
AU - Rao, Dabeeru C.
AU - Morrison, Alanna C.
N1 - Publisher Copyright: © The Author(s) 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 - 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
SN - 0002-9262
VL - 188
SP - 1033
EP - 1054
JO - American journal of epidemiology
JF - American journal of epidemiology
IS - 6
ER -