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

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

Research output: Contribution to journalArticlepeer-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 languageEnglish (US)
Pages (from-to)1033-1054
Number of pages22
JournalAmerican journal of epidemiology
Volume188
Issue number6
DOIs
StatePublished - Jun 1 2019
Externally publishedYes

Keywords

  • Alcohol Consumption
  • Cholesterol
  • Gene-Environment Interactions
  • Gene-Lifestyle Interactions
  • Genome-Wide Association Studies
  • Lipids
  • Triglycerides

ASJC Scopus subject areas

  • Epidemiology

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