Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Tuomas O. Kilpeläinen (), Amy R. Bentley, Raymond Noordam, Yun Ju Sung, Karen Schwander, Thomas W. Winkler, Hermina Jakupović, Daniel I. Chasman, Alisa Manning, Ioanna Ntalla, Hugues Aschard, Michael R. Brown, Lisa las Fuentes, Nora Franceschini, Xiuqing Guo, Dina Vojinovic, Stella Aslibekyan, Mary F. Feitosa, Minjung Kho, Solomon K. Musani, Melissa Richard, Heming Wang, Zhe Wang, Traci M. Bartz, Lawrence F. Bielak, Archie Campbell, Rajkumar Dorajoo, Virginia Fisher, Fernando P. Hartwig, Andrea R. V. R. Horimoto, Changwei Li, Kurt K. Lohman, Jonathan Marten, Xueling Sim, Albert V. Smith, Salman M. Tajuddin, Maris Alver, Marzyeh Amini, Mathilde Boissel, Jin Fang Chai, Xu Chen, Jasmin Divers, Evangelos Evangelou, Chuan Gao, Mariaelisa Graff, Sarah E. Harris, Meian He, Fang-Chi Hsu, Anne U. Jackson, Jing Hua Zhao, Aldi T. Kraja, Brigitte Kühnel, Federica Laguzzi, Leo-Pekka Lyytikäinen, Ilja M. Nolte, Rainer Rauramaa, Muhammad Riaz, Antonietta Robino, Rico Rueedi, Heather M. Stringham, Fumihiko Takeuchi, Peter J. Most, Tibor V. Varga, Niek Verweij, Erin B. Ware, Wanqing Wen, Xiaoyin Li, Lisa R. Yanek, Najaf Amin, Donna K. Arnett, Eric Boerwinkle, Marco Brumat, Brian Cade, Mickaël Canouil, Yii- Der Ida Chen, Maria Pina Concas, John Connell, Renée Mutsert, H. Janaka Silva, Paul S. Vries, Ayşe Demirkan, Jingzhong Ding, Charles B. Eaton, Jessica D. Faul, Yechiel Friedlander, Kelley P. Gabriel, Mohsen Ghanbari, Franco Giulianini, Chi Charles Gu, Dongfeng Gu, Tamara B. Harris, Jiang He, Sami Heikkinen, Chew-Kiat Heng, Steven C. Hunt, M. Arfan Ikram, Jost B. Jonas, Woon-Puay Koh, Pirjo Komulainen, Jose E. Krieger, Stephen B. Kritchevsky, Zoltán Kutalik, Johanna Kuusisto, Carl D. Langefeld, Claudia Langenberg, Lenore J. Launer, Karin Leander, Rozenn N. Lemaitre, Cora E. Lewis, Jingjing Liang, Jianjun Liu, Reedik Mägi, Ani Manichaikul, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Karen L. Mohlke, Thomas H. Mosley, Alison D. Murray, Mike A. Nalls, Ei-Ei Khaing Nang, Christopher P. Nelson, Sotoodehnia Nona, Jill M. Norris, Chiamaka Vivian Nwuba, Jeff O’Connell, Nicholette D. Palmer, George J. Papanicolau, Raha Pazoki, Nancy L. Pedersen, Annette Peters, Patricia A. Peyser, Ozren Polasek, David J. Porteous, Alaitz Poveda, Olli T. Raitakari, Stephen S. Rich, Neil Risch, Jennifer G. Robinson, Lynda M. Rose, Igor Rudan, Pamela J. Schreiner, Robert A. Scott, Stephen S. Sidney, Mario Sims, Jennifer A. Smith, Harold Snieder, Tamar Sofer, John M. Starr, Barbara Sternfeld, Konstantin Strauch, Hua Tang, Kent D. Taylor, Michael Y. Tsai, Jaakko Tuomilehto, André G. Uitterlinden, M. Yldau Ende, Diana Heemst, Trudy Voortman, Melanie Waldenberger, Patrik Wennberg, Gregory Wilson, Yong-Bing Xiang, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Alan B. Zonderman, Diane M. Becker, Michael Boehnke, Donald W. Bowden, Ulf Faire, Ian J. Deary, Paul Elliott, Tõnu Esko, Barry I. Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Norihiro Kato, Markku Laakso, Timo A. Lakka, Terho Lehtimäki, Patrik K. E. Magnusson, Albertine J. Oldehinkel, Brenda W. J. H. Penninx, Nilesh J. Samani, Xiao-Ou Shu, Pim Harst, Jana V. Vliet-Ostaptchouk, Peter Vollenweider, Lynne E. Wagenknecht, Ya X. Wang, Nicholas J. Wareham, David R. Weir, Tangchun Wu, Wei Zheng, Xiaofeng Zhu, Michele K. Evans, Paul W. Franks, Vilmundur Gudnason, Caroline Hayward, Bernardo L. Horta, Tanika N. Kelly, Yongmei Liu, Kari E. North, Alexandre C. Pereira, Paul M. Ridker, E. Shyong Tai, Rob M. Dam, Ervin R. Fox, Sharon L. R. Kardia, Ching-Ti Liu, Dennis O. Mook-Kanamori, Michael A. Province, Susan Redline, Cornelia M. Duijn, Jerome I. Rotter, Charles B. Kooperberg, W. James Gauderman, Bruce M. Psaty, Kenneth Rice, Patricia B. Munroe, Myriam Fornage, L. Adrienne Cupples, Charles N. Rotimi, Alanna C. Morrison, Dabeeru C. Rao () and Ruth J. F. Loos ()
Additional contact information
Tuomas O. Kilpeläinen: University of Copenhagen
Amy R. Bentley: National Institutes of Health
Raymond Noordam: Leiden University Medical Center
Yun Ju Sung: Washington University School of Medicine
Karen Schwander: Washington University School of Medicine
Thomas W. Winkler: University of Regensburg
Hermina Jakupović: University of Copenhagen
Daniel I. Chasman: Brigham and Women’s Hospital
Alisa Manning: Massachusetts General Hospital
Ioanna Ntalla: Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Hugues Aschard: Harvard School of Public Health
Michael R. Brown: The University of Texas Health Science Center at Houston
Lisa las Fuentes: Washington University School of Medicine
Nora Franceschini: Epidemiology, University of North Carolina Gillings School of Global Public Health
Xiuqing Guo: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Dina Vojinovic: Erasmus University Medical Center
Stella Aslibekyan: University of Alabama at Birmingham
Mary F. Feitosa: Washington University School of Medicine
Minjung Kho: University of Michigan
Solomon K. Musani: University of Mississippi Medical Center
Melissa Richard: University of Texas Health Science Center at Houston
Heming Wang: Brigham and Women’s Hospital
Zhe Wang: The University of Texas Health Science Center at Houston
Traci M. Bartz: University of Washington
Lawrence F. Bielak: University of Michigan
Archie Campbell: University of Edinburgh
Rajkumar Dorajoo: Agency for Science Technology and Research
Virginia Fisher: Biostatistics, Boston University School of Public Health
Fernando P. Hartwig: Federal University of Pelotas
Andrea R. V. R. Horimoto: University of São Paulo Medical School
Changwei Li: University of Giorgia at Athens College of Public Health
Kurt K. Lohman: Wake Forest University Health Sciences
Jonathan Marten: University of Edinburgh
Xueling Sim: National University Health System and National University of Singapore
Albert V. Smith: Icelandic Heart Association
Salman M. Tajuddin: National Institute on Aging, National Institutes of Health
Maris Alver: University of Tartu
Marzyeh Amini: University Medical Center Groningen
Mathilde Boissel: Institut Pasteur de Lille, University of Lille
Jin Fang Chai: National University Health System and National University of Singapore
Xu Chen: Karolinska Institutet, Stockholm
Jasmin Divers: Wake Forest School of Medicine
Evangelos Evangelou: Imperial College London
Chuan Gao: Wake Forest School of Medicine
Mariaelisa Graff: Epidemiology, University of North Carolina Gillings School of Global Public Health
Sarah E. Harris: University of Edinburgh
Meian He: Huazhong University of Science and Technology
Fang-Chi Hsu: Wake Forest School of Medicine
Anne U. Jackson: University of Michigan
Jing Hua Zhao: University of Cambridge
Aldi T. Kraja: Washington University School of Medicine
Brigitte Kühnel: Helmholtz Zentrum München, German Research Center for Environmental Health
Federica Laguzzi: Karolinska Institutet
Leo-Pekka Lyytikäinen: Fimlab Laboratories
Ilja M. Nolte: University Medical Center Groningen
Rainer Rauramaa: Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine
Muhammad Riaz: The Infant Mortality and Morbidity Studies (TIMMS)
Antonietta Robino: Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”
Rico Rueedi: University of Lausanne
Heather M. Stringham: University of Michigan
Fumihiko Takeuchi: National Center for Global Health and Medicine
Peter J. Most: University Medical Center Groningen
Tibor V. Varga: Skåne University Hospital
Niek Verweij: University of Groningen, University Medical Center Groningen, Department of Cardiology
Erin B. Ware: University of Michigan
Wanqing Wen: Vanderbilt University School of Medicine
Xiaoyin Li: Case Western Reserve University
Lisa R. Yanek: Johns Hopkins University School of Medicine
Najaf Amin: Erasmus University Medical Center
Donna K. Arnett: University of Kentucky College of Public Health
Eric Boerwinkle: The University of Texas Health Science Center at Houston
Marco Brumat: University of Trieste
Brian Cade: Brigham and Women’s Hospital
Mickaël Canouil: Institut Pasteur de Lille, University of Lille
Yii- Der Ida Chen: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Maria Pina Concas: Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”
John Connell: University of Dundee
Renée Mutsert: Leiden University Medical Center
H. Janaka Silva: University of Kelaniya
Paul S. Vries: The University of Texas Health Science Center at Houston
Ayşe Demirkan: Erasmus University Medical Center
Jingzhong Ding: Wake Forest School of Medicine
Charles B. Eaton: Alpert Medical School of Brown University
Jessica D. Faul: University of Michigan
Yechiel Friedlander: Hebrew University-Hadassah Medical Center
Kelley P. Gabriel: The University of Texas Health Science Center at Austin
Mohsen Ghanbari: Erasmus University Medical Center
Franco Giulianini: Brigham and Women’s Hospital
Chi Charles Gu: Washington University School of Medicine
Dongfeng Gu: Chinese Academy of Medical Sciences and Peking Union Medical College
Tamara B. Harris: National Institutes of Health
Jiang He: Epidemiology, Tulane University School of Public Health and Tropical Medicine
Sami Heikkinen: University of Eastern Finland
Chew-Kiat Heng: National University of Singapore
Steven C. Hunt: University of Utah
M. Arfan Ikram: Erasmus University Medical Center
Jost B. Jonas: University Heidelberg
Woon-Puay Koh: National University Health System and National University of Singapore
Pirjo Komulainen: Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine
Jose E. Krieger: University of São Paulo Medical School
Stephen B. Kritchevsky: Wake Forest School of Medicine
Zoltán Kutalik: Swiss Institute of Bioinformatics
Johanna Kuusisto: University of Eastern Finland
Carl D. Langefeld: Wake Forest School of Medicine
Claudia Langenberg: University of Cambridge
Lenore J. Launer: National Institutes of Health
Karin Leander: Karolinska Institutet
Rozenn N. Lemaitre: University of Washington
Cora E. Lewis: University of Alabama at Birmingham, School of Medicine
Jingjing Liang: Case Western Reserve University
Jianjun Liu: Agency for Science Technology and Research
Reedik Mägi: University of Tartu
Ani Manichaikul: University of Virginia School of Medicine
Thomas Meitinger: Helmholtz Zentrum München, German Research Center for Environmental Health
Andres Metspalu: University of Tartu
Yuri Milaneschi: VU University Medical Center
Karen L. Mohlke: University of North Carolina
Thomas H. Mosley: University of Mississippi
Alison D. Murray: University of Aberdeen
Mike A. Nalls: National Institute on Aging
Ei-Ei Khaing Nang: National University Health System and National University of Singapore
Christopher P. Nelson: University of Leicester
Sotoodehnia Nona: University of Washington
Jill M. Norris: University of Colorado Denver
Chiamaka Vivian Nwuba: University of Copenhagen
Jeff O’Connell: University of Maryland School of Medicine
Nicholette D. Palmer: Wake Forest School of Medicine
George J. Papanicolau: National Institutes of Health
Raha Pazoki: Imperial College London
Nancy L. Pedersen: Karolinska Institutet, Stockholm
Annette Peters: German Research Center for Environmental Health
Patricia A. Peyser: University of Michigan
Ozren Polasek: University of Split
David J. Porteous: University of Edinburgh
Alaitz Poveda: Skåne University Hospital
Olli T. Raitakari: Turku University Hospital
Stephen S. Rich: University of Virginia School of Medicine
Neil Risch: University of California
Jennifer G. Robinson: University of Iowa
Lynda M. Rose: Brigham and Women’s Hospital
Igor Rudan: University of Edinburgh
Pamela J. Schreiner: University of Minnesota
Robert A. Scott: University of Cambridge
Stephen S. Sidney: Kaiser Permanente Washington, Health Research Institute
Mario Sims: University of Mississippi Medical Center
Jennifer A. Smith: University of Michigan
Harold Snieder: University Medical Center Groningen
Tamar Sofer: Harvard Medical School
John M. Starr: The University of Edinburgh
Barbara Sternfeld: Kaiser Permanente Washington, Health Research Institute
Konstantin Strauch: German Research Center for Environmental Health
Hua Tang: Stanford University
Kent D. Taylor: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Michael Y. Tsai: University of Minnesota
Jaakko Tuomilehto: National Institute for Health and Welfare
André G. Uitterlinden: Erasmus University Medical Center
M. Yldau Ende: University of Groningen, University Medical Center Groningen, Department of Cardiology
Diana Heemst: Leiden University Medical Center
Trudy Voortman: Erasmus University Medical Center
Melanie Waldenberger: Helmholtz Zentrum München, German Research Center for Environmental Health
Patrik Wennberg: Umeå University
Gregory Wilson: Jackson State University
Yong-Bing Xiang: Shanghai Jiaotong University School of Medicine
Jie Yao: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Caizheng Yu: Huazhong University of Science and Technology
Jian-Min Yuan: University of Pittsburgh
Wei Zhao: University of Michigan
Alan B. Zonderman: National Institutes of Health
Diane M. Becker: Johns Hopkins University School of Medicine
Michael Boehnke: University of Michigan
Donald W. Bowden: Wake Forest School of Medicine
Ulf Faire: Karolinska Institutet
Ian J. Deary: The University of Edinburgh
Paul Elliott: Imperial College London
Tõnu Esko: University of Tartu
Barry I. Freedman: Wake Forest School of Medicine
Philippe Froguel: Institut Pasteur de Lille, University of Lille
Paolo Gasparini: Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”
Christian Gieger: Helmholtz Zentrum München, German Research Center for Environmental Health
Norihiro Kato: National Center for Global Health and Medicine
Markku Laakso: University of Eastern Finland
Timo A. Lakka: Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine
Terho Lehtimäki: Fimlab Laboratories
Patrik K. E. Magnusson: Karolinska Institutet, Stockholm
Albertine J. Oldehinkel: University Medical Center Groningen
Brenda W. J. H. Penninx: VU University Medical Center
Nilesh J. Samani: University of Leicester
Xiao-Ou Shu: Vanderbilt University School of Medicine
Pim Harst: University of Groningen, University Medical Center Groningen, Department of Cardiology
Jana V. Vliet-Ostaptchouk: University Medical Center Groningen
Peter Vollenweider: Lausanne University Hospital
Lynne E. Wagenknecht: Wake Forest School of Medicine
Ya X. Wang: Capital Medical University
Nicholas J. Wareham: University of Cambridge
David R. Weir: University of Michigan
Tangchun Wu: Huazhong University of Science and Technology
Wei Zheng: Vanderbilt University School of Medicine
Xiaofeng Zhu: Case Western Reserve University
Michele K. Evans: National Institute on Aging, National Institutes of Health
Paul W. Franks: Skåne University Hospital
Vilmundur Gudnason: Icelandic Heart Association
Caroline Hayward: University of Edinburgh
Bernardo L. Horta: Federal University of Pelotas
Tanika N. Kelly: Epidemiology, Tulane University School of Public Health and Tropical Medicine
Yongmei Liu: Wake Forest University Health Sciences
Kari E. North: Epidemiology, University of North Carolina Gillings School of Global Public Health
Alexandre C. Pereira: University of São Paulo Medical School
Paul M. Ridker: Brigham and Women’s Hospital
E. Shyong Tai: National University Health System and National University of Singapore
Rob M. Dam: National University Health System and National University of Singapore
Ervin R. Fox: University of Mississippi Medical Center
Sharon L. R. Kardia: University of Michigan
Ching-Ti Liu: Biostatistics, Boston University School of Public Health
Dennis O. Mook-Kanamori: Leiden University Medical Center
Michael A. Province: Washington University School of Medicine
Susan Redline: Brigham and Women’s Hospital
Cornelia M. Duijn: Erasmus University Medical Center
Jerome I. Rotter: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Charles B. Kooperberg: University of Washington School of Public Health
W. James Gauderman: University of Southern California
Bruce M. Psaty: Kaiser Permanente Washington, Health Research Institute
Kenneth Rice: University of Washington
Patricia B. Munroe: Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Myriam Fornage: University of Texas Health Science Center at Houston
L. Adrienne Cupples: Biostatistics, Boston University School of Public Health
Charles N. Rotimi: National Institutes of Health
Alanna C. Morrison: The University of Texas Health Science Center at Houston
Dabeeru C. Rao: Washington University School of Medicine
Ruth J. F. Loos: The Charles Bronfman Institute for Personalized Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

Date: 2019
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DOI: 10.1038/s41467-018-08008-w

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