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

de Vries, Paul S; Brown, Michael R; Bentley, Amy R; Sung, Yun J; Winkler, Thomas W; Ntalla, Ioanna; Schwander, Karen; Kraja, Aldi T; Guo, Xiuqing; Franceschini, Nora; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Huffman, Jennifer E; Musani, Solomon K; Li, Changwei; Feitosa, Mary F; Richard, Melissa A; Noordam, Raymond; Aschard, Hugues; Bartz, Traci M; Bielak, Lawrence F; Deng, Xuan; Dorajoo, Rajkumar; Lohman, Kurt K; Manning, Alisa K; Rankinen, Tuomo; Smith, Albert V; Tajuddin, Salman M; Evangelou, Evangelos; Graff, Mariaelisa; Alver, Maris; Boissel, Mathilde; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Gandin, Ilaria; Gao, Chuan; Goel, Anuj; Hagemeijer, Yanick; Harris, Sarah E; Hartwig, Fernando P; He, Meian; Horimoto, Andrea R V R; Hsu, Fang-Chi; Jackson, Anne U; Kasturiratne, Anuradhani; Komulainen, Pirjo; Kühnel, Brigitte; Laguzzi, Federica; Lee, Joseph H; Luan, Jian'an; Lyytikäinen, Leo-Pekka; Matoba, Nana; Nolte, Ilja M; Pietzner, Maik; Riaz, Muhammad; Said, M Abdullah; Scott, Robert A; Sofer, Tamar; Stančáková, Alena; Takeuchi, Fumihiko; Tayo, Bamidele O; van der Most, Peter J; Varga, Tibor V; Wang, Yajuan; Ware, Erin B; Wen, Wanqing; Yanek, Lisa R; Zhang, Weihua; Zhao, Jing Hua; Afaq, Saima; Amin, Najaf; Amini, Marzyeh; Arking, Dan E; Aung, Tin; Ballantyne, Christie; Boerwinkle, Eric; Broeckel, Ulrich; Campbell, Archie; Canouil, Mickaël; Charumathi, Sabanayagam; Chen, Yii-Der Ida; Connell, John M; de Faire, Ulf; de las Fuentes, Lisa; de Mutsert, Renée; de Silva, H Janaka; Ding, Jingzhong; Dominiczak, Anna F; Duan, Qing; Eaton, Charles B; Eppinga, Ruben N; Faul, Jessica D; Fisher, Virginia; Forrester, Terrence; Franco, Oscar H; Friedlander, Yechiel; Ghanbari, Mohsen; Giulianini, Franco; Grabe, Hans J; Grove, Megan L; Gu, C Charles; Harris, Tamara B; Heikkinen, Sami; Heng, Chew-Kiat; Hirata, Makoto; Hixson, James E; Howard, Barbara V; Ikram, M Arfan; Jacobs, David R; Johnson, Craig; Jonas, Jost Bruno; Kammerer, Candace M; Katsuya, Tomohiro; Khor, Chiea Chuen; Kilpeläinen, Tuomas O; Koh, Woon-Puay; Koistinen, Heikki A; Kolcic, Ivana; Kooperberg, Charles; Krieger, Jose E; Kritchevsky, Steve B; Kubo, Michiaki; Kuusisto, Johanna; Lakka, Timo A; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lehne, Benjamin; Lemaitre, Rozenn N; Li, Yize; Liang, Jingjing; Liu, Jianjun; Liu, Kiang; Loh, Marie; Louie, Tin; Mägi, Reedik; Manichaikul, Ani W; McKenzie, Colin A; Meitinger, Thomas; Metspalu, Andres; Milaneschi, Yuri; Milani, Lili; Mohlke, Karen L; Mosley, Thomas H; Mukamal, Kenneth J; Nalls, Mike A; Nauck, Matthias; Nelson, Christopher P; Sotoodehnia, Nona; O'Connell, Jeff R; Palmer, Nicholette D; Pazoki, Raha; Pedersen, Nancy L; Peters, Annette; Peyser, Patricia A; Polasek, Ozren; Poulter, Neil; Raffel, Leslie J; Raitakari, Olli T; Reiner, Alex P; Rice, Treva K; Rich, Stephen S; Robino, Antonietta; Robinson, Jennifer G; Rose, Lynda M; Rudan, Igor; Schmidt, Carsten O; Schreiner, Pamela J; Scott, William R; Sever, Peter; Shi, Yuan; Sidney, Stephen; Sims, Mario; Smith, Blair H; Smith, Jennifer A; Snieder, Harold; Starr, John M; Strauch, Konstantin; Tan, Nicholas; Taylor, Kent D; Teo, Yik Ying; Tham, Yih Chung; Uitterlinden, André G; van Heemst, Diana; Vuckovic, Dragana; Waldenberger, Melanie; Wang, Lihua; Wang, Yujie; Wang, Zhe; Wei, Wen Bin; Williams, Christine; Wilson, Gregory; Wojczynski, Mary K; Yao, Jie; Yu, Bing; Yu, Caizheng; Yuan, Jian-Min; Zhao, Wei; Zonderman, Alan B; Becker, Diane M; Boehnke, Michael; Bowden, Donald W; Chambers, John C; Deary, Ian J; Esko, Tõnu; Farrall, Martin; Franks, Paul W; Freedman, Barry I; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Horta, Bernardo L; Kamatani, Yoichiro; Kato, Norihiro; Kooner, Jaspal S; Laakso, Markku; Leander, Karin; Lehtimäki, Terho; Magnusson, Patrik K E; Penninx, Brenda; Pereira, Alexandre C; Rauramaa, Rainer; Samani, Nilesh J; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E; Wang, Ya Xing; Wareham, Nicholas J; Watkins, Hugh; Weir, David R; Wickremasinghe, Ananda R; Zheng, Wei; Elliott, Paul; North, Kari E; Bouchard, Claude; Evans, Michele K; Gudnason, Vilmundur; Liu, Ching-Ti; Liu, Yongmei; Psaty, Bruce M; Ridker, Paul M; van Dam, Rob M; Kardia, Sharon L R; Zhu, Xiaofeng; Rotimi, Charles N; Mook-Kanamori, Dennis O; Fornage, Myriam; Kelly, Tanika N; Fox, Ervin R; Hayward, Caroline; van Duijn, Cornelia M; Tai, E Shyong; Wong, Tien Yin; Liu, Jingmin; Rotter, Jerome I; Gauderman, W James; Province, Michael A; Munroe, Patricia B; Rice, Kenneth; Chasman, Daniel I; Cupples, L Adrienne; Rao, Dabeeru C and Morrison, Alanna C (2019). Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. American Journal of Epidemiology, 188(6) pp. 1033–1054.

DOI: https://doi.org/10.1093/aje/kwz005

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.

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