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

Zhe Wang*, Andrew Emmerich, The LifeLines Cohort Study, 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, Åsa Johansson, Anja Moltke Jørgensen, Marika A. Kaakinen, Robert Karlsson, Kathleen F. Kerr, Boram Kim, Chantal M. Koolhaas, Zoltan Kutalik, Vasiliki Lagou, Penelope A. Lind, Rebecca C. Richmond, Alexander Teumer, Jing Hua Zhao, Wei Zhao, Andre G. Uitterlinden, M. Carola Zillikens, Torben Hansen, Nathalie van der Velde, Cornelia M. van Duijn, Trudy Voortman, FJA van Rooij, Oscar Franco Duran, Ruth J.F. Loos, M den Hoed

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

53 Citations (Scopus)
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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.

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

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Open access funding provided by Uppsala University

Publisher Copyright: © 2022, The Author(s).


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