Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention

Zhe Wang, The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. zhe.wang@mssm.edu.
Andrew Emmerich, Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
Nicolas J. Pillon, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Tim Moore, Division of Cardiology, Department of Medicine, University of California, Los Angeles, CA, USA.
Daiane Hemerich, The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Marilyn C. Cornelis, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Eugenia Mazzaferro, The Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala, Sweden.
Siacia Broos, Faculty of Movement and Rehabilitation Sciences, Department of Movement Sciences - Exercise Physiology Research Group, KU Leuven, Leuven, Belgium.
Tarunveer S. Ahluwalia, Steno Diabetes Center Copenhagen, Herlev, Denmark.
Traci M. Bartz, Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Amy R. Bentley, Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Lawrence F. Bielak, Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Mike Chong, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Audrey Y. Chu, Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Diane Berry, Division of Population, Policy and Practice, Great Ormond Street Hospital Institute for Child Health, University College London, London, UK.
Rajkumar Dorajoo, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore.
Nicole D. Dueker, John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Elisa Kasbohm, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Bjarke Feenstra, Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Mary F. Feitosa, Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
Christian Gieger, Research Unit of Molecular Epidemiology, Helmholtz Zentrum München -Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Munich, Germany.
Mariaelisa Graff, Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
Leanne M. Hall, Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
Toomas Haller, Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
Fernando P. Hartwig, Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil.
David A. Hillis, Genetics, Genomics, and Bioinformatics Graduate Program, University of California, Riverside, CA, USA.
Ville Huikari, Institute of Health Sciences, University of Oulu, Oulu, Finland.
Nancy Heard-Costa, Framingham Heart Study, Framingham, MA, USA.
Christina Holzapfel, Research Unit of Molecular Epidemiology, Helmholtz Zentrum München -Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Munich, Germany.
Anne U. Jackson, Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
Åsa Johansson, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Anja Moltke Jørgensen, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Document Type

Journal Article

Publication Date

9-1-2022

Journal

Nature genetics

Volume

54

Issue

9

DOI

10.1038/s41588-022-01165-1

Abstract

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type II muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

Department

Exercise and Nutrition Sciences

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