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

Lifelines Cohort Study, Zhe Wang, Andrew Emmerich, Nicolas J. Pillon, Tim Moore, Daiane Hemerich, Marilyn C. Cornelis, Eugenia Mazzaferro, Siacia Broos, Tarunveer S. Ahluwalia, Traci M. Bartz, Amy R. Bentley, Lawrence F. Bielak, Mike Chong, Audrey Y. Chu, Diane Berry, Rajkumar Dorajoo, Nicole D. Dueker, Elisa Kasbohm, Bjarke FeenstraMary F. Feitosa, Christian Gieger, Mariaelisa Graff, Leanne M. Hall, Toomas Haller, Fernando P. Hartwig, David A. Hillis, Ville Huikari, Nancy Heard-Costa, Christina Holzapfel, Anne U. Jackson, Asa Johansson, Anja Moltke Jorgensen, Marika A. Kaakinen, Robert Karlsson, Kathleen F. Kerr, Boram Kim, Chantal M. Koolhaas, Zoltan Kutalik, Vasiliki Lagou, Peter J. Van der Most, Jana V. Van Vliet-Ostaptchouk, Jing-Hua Zhao, Wei Zhao, Marcel Bruinenberg, Catharina A. Hartman, Ilja M. Nolte, Albert Smith, Albertine J. Oldehinkel, Brenda W. J. H. Penninx, Harold Snieder

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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 IIA 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.

Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.

Original languageEnglish
Pages (from-to)1332–1344
Number of pages13
JournalNature genetics
Issue number9
Publication statusPublished - Sept-2022


  • Actinin/genetics
  • Cross-Sectional Studies
  • Exercise/physiology
  • Genome-Wide Association Study
  • Humans
  • Leisure Activities
  • Sedentary Behavior

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