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

15 Scopus citations

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

Bibliographical note

Funding Information:
Rotterdam Study: The Rotterdam Study was funded by Erasmus Medical Center (Erasmus MC) and Erasmus University (Rotterdam, the Netherlands), the Netherlands Organisation for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (Directorate-General for Science Research and Development (DG XII)), and the Municipality of Rotterdam. Generation and management of GWAS genotype data for the Rotterdam Study was conducted at the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC. The GWAS data sets were supported by the NWO (grants 175.010.2005.011 and 911-03-012); the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC; the Research Institute for Diseases in the Elderly (RIDE2 grant 014-93-015); the Netherlands Genomics Initiative/NWO; and the Netherlands Consortium for Healthy Aging (project 050-060-810). Singapore Chinese Eye Study, Singapore Malay Eye Study, and Singapore Indian Eye Study: The Singapore Malay Eye Study, the Singapore Indian Eye Study, and the Singapore Chinese Eye Study were supported by the National Medical Research Council (Singapore) (grants 0796/2003, 1176/2008, 1149/2008, STAR/0003/2008, 1249/2010, CG/SERI/2010, CIRG/1371/ 2013, and CIRG/1417/2015) and the Biomedical Research Council (Singapore) (grants 08/1/35/19/550 and 09/1/35/19/ 616). Ching-Yu Cheng was supported by an award from the National Medical Research Council (grant CSA/033/2012). The Singapore Tissue Network and the Genome Institute of Singapore (Agency for Science, Technology and Research, Singapore) provided services for tissue archival and genotyping, respectively. Singapore Chinese Health Study– Coronary Heart Disease Study: The Singapore Chinese Health Study was supported by the NIH (grants RO1 CA144034 and UM1 CA182876); the Coronary Heart Disease Study, a nested case-control study of myocardial infarction, was supported by the National Medical Research Council (Singapore) (grant 1270/2010); and genotyping was supported by the Hebrew University of Jerusalem–Campus for Research Excellence and Technological Enterprise (HUJ-CREATE) Programme of the National Research Foundation (Singapore) (project 370062002). Singapore 2 (SP2) Prospective Study Program: The SP2 Study (including the SP2-1M and SP2-610 subsets) was supported by individual research grants and clinician scientist awards from the National Medical Research Council (Singapore) and the Biomedical Research Council (Singapore). Women’sGenome Health Study: The Women’s Genome Health Study was supported by the NHLBI (grants HL043851 and HL080467) and the National Cancer Institute, NIH (grants CA047988 and UM1CA182913), with collaborative scientific support and funding for genotyping provided by Amgen, Inc. (Thousand Oaks, California). Women’s Health Initiative: The Women’s Health Initiative was funded by the NHLBI through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C.

Funding Information:
Stage 2 studies—African American Diabetes Heart Study: The African American Diabetes Heart Study was supported by NIH grants R01 DK071891 and R01 HL092301 and the General Clinical Research Center of Wake Forest School of Medicine, Wake Forest University (grant M01-RR-07122). Airwave Health Monitoring Study: The Airwave Health Monitoring Study was funded by the United Kingdom Home Office (grant 780-TETRA), with additional support from the National Institute for Health Research (NIHR), the Imperial College Healthcare NHS Trust, and the Imperial College Biomedical Research Centre. The study received ethical approval from the National Health Service Multicentre Research Ethics Committee. This work used computing resources provided by the MRC-funded UK Medical Bioinformatics Partnership Programme (grant MR/ L01632X/1). Paul Elliott received support from the Medical Research Council and Public Health England for the MRC-PHE Centre for Environment and Health (grant MR/ L01341X/1) and from the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (grant HPRU-2012-10141). Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT): ASCOT and the collection of samples for the ASCOT DNA repository were supported by Pfizer, Inc. (New York, New York); by the Servier Research Group (Paris, France); and by Leo Laboratories (Copenhagen, Denmark). Genotyping was funded by the Centre National de Génotypage, the Medical Research Council, and the NIHR. This work forms part of the research program of the NIHR Cardiovascular Biomedical Research Unit (NIHR Barts Biomedical Research Centre) at Barts and The London School of Medicine and Dentistry, Queen Mary University of London. Practicia B. Munroe received support from the NIHR Barts Biomedical Research Centre at Barts and The London School of Medicine and Dentistry, Queen Mary University of London. Beijing Eye Study: The Beijing Eye Study was supported by the National Key Laboratory Fund, Beijing, China. BioBank Japan Project: The BioBank Japan Project was supported by the Japan Agency for Medical Research and Development and by the Japanese Ministry of Education, Culture, Sports, Sciences and Technology. British Genetics of Hypertension (BRIGHT) Study: The BRIGHT Study was supported by the Medical Research Council (grant G9521010D) and the British Heart Foundation (grant PG/02/128) and forms part of the research program of the NIHR Cardiovascular Biomedical Unit (NIHR Barts Biomedical Research Centre) at Barts and The London School of Medicine and Dentistry, Queen Mary University of London. Cardio-metabolic Genome Epidemiology Network Amagasaki (CAGE-Amagasaki) Study: The Cardio-metabolic Genome Epidemiology Network studies were supported by Core Research for Evolutional Science and Technology (CREST) grants from the Japan Science and Technology Agency; the Program for Promotion of Fundamental Studies in Health Sciences, National Institute of Biomedical Innovation (Japan); and a grant from the National Center for Global Health and Medicine (Japan). Cooperative Health Research in the Augsburg Region (KORA) Study: The KORA Study was initiated and financed by the German Research Center for Environmental Health (Helmholtz Zentrum München), which is supported by the German Federal Ministry of Education and Research and the State of Bavaria.

Funding Information:
We declare no competing financial interests, except for the following. B.M.P. serves on the Data and Safety Monitoring Board of a clinical trial funded by the manufacturer (Zoll Lifecor Corporation, Pittsburgh, Pennsylvania) and on the Steering Committee of the Yale Open Data Access Project, funded by Johnson & Johnson (New Brunswick, New Jersey). O.H.F. received grants from Metagenics, Inc. (Aliso Viejo, California) on women’s health and epigenetics and from Nestlé S.A. (Vevey, Switzerland) on child health. M.A.N.’s participation was supported by a consulting contract between Data Tecnica International (Glen Echo, Maryland) and the NIA (Bethesda, Maryland). M.A.N. also consults for Illumina Inc. (San Diego, California), the Michael J. Fox Foundation for Parkinson’s Research (New York, New York), and UC Health (Oakland, California), among other organizations. N.P. has received financial support and consultancy fees from several pharmaceutical companies that manufacture either blood pressure-lowering or lipid-lowering agents or both (Sanofi (Guildford, United Kingdom), Amgen (Uxbridge, United Kingdom), Takeda (London, United Kingdom), Servier (Suresnes, France), and Pfizer (Tadwork, United Kingdom)) but holds no stock or shares in any such companies. P.S. has received research awards from Pfizer Inc. (New York, New York). J.B.J. serves as a consultant for the Mundipharma Company (Cambridge, United Kingdom), is a patent holder with Biocompatibles UK Ltd. (Franham, United Kingdom) (patent no. 20120263794; “Treatment of Eye Diseases Using Encapsulated Cells Encoding and Secreting Neuroprotective Factor and/or Anti-Angiogenic Factor”), and is a patent applicant with the University of Heidelberg (Heidelberg, Germany) (Europäische Patentanmeldung no. 15 000 771.4; “Agents for Use in the Therapeutic or Prophylactic Treatment of Myopia or Hyperopia”).

Keywords

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

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