Tuomas O. Kilpeläinen, University of Copenhagen, Denmark
Amy R. Bentley, National Human Genome Research Institute
Raymond Noordam, Leiden University, The Netherlands
Yun Ju Sung, Washington University in St. Louis
Karen Schwander, Washington University in St. Louis
Thomas W. Winkler, University of Regensburg, Germany
Hermina Jakupović, University of Copenhagen, Denmark
Daniel I. Chasman, Harvard University
Alisa Manning, Massachusetts General Hospital
Ioanna Ntalla, Queen Mary University of London, UK
Hugues Aschard, Harvard University
Michael R. Brown, The University of Texas Health Science Center at Houston
Lisa de las Fuentes, Washington University in St. Louis
Nora Franceschini, University of North Carolina at Chapel Hill
Xiuqing Guo, Harbor-UCLA Medical Center
Dina Vojinovic, Erasmus University, The Netherlands
Stella Aslibekyan, University of Alabama at Birmingham
Mary F. Feitosa, Washington University in St. Louis
Minjung Kho, University of Michigan - Ann Arbor
Solomon K. Musani, University of Mississippi
Melissa Richard, The 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 - Ann Arbor
Archie Campbell, University of Edinburgh, UK
Rajkumar Dorajoo, Agency for Science Technology and Research, Singapore
Virginia Fisher, Boston University
Fernando P. Hartwig, Federal University of Pelotas, Brazil
Andrea R. V. R. Horimoto, University of São Paulo, Brazil
Donna K. Arnett, University of KentuckyFollow


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.

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Notes/Citation Information

Published in Nature Communications, v. 10, article no. 376, p. 1-11.

© The Author(s) 2019

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Funding Information

The present work was largely supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305).

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The meta-analysis summary results are available for download on the CHARGE dbGaP website under accession phs000930.

Supplementary Information accompanies this paper at 018-08008-w.

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