Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention
Authors: Wang Zhe , Emmerich Andrew , Pillon Nicolas J. , Moore Tim , Hemerich Daiane , Cornelis Marilyn C. , Mazzaferro Eugenia , Broos Siacia , Ahluwalia Tarunveer S. , Bartz Traci M. , Bentley Amy R. , Bielak Lawrence F. , Chong Mike , Chu Audrey Y. , Berry Diane , Dorajoo Rajkumar , Dueker Nicole D. , Kasbohm Elisa , Feenstra Bjarke , Feitosa Mary F. , Gieger Christian , Graff Mariaelisa , Hall Leanne M. , Haller Toomas , Hartwig Fernando P. , Hillis David A. , Huikari Ville , Heard-Costa Nancy , Holzapfel Christina , Jackson Anne U. , Johansson Åsa , Jørgensen Anja Moltke , Kaakinen Marika A. , Karlsson Robert , Kerr Kathleen F. , Kim Boram , Koolhaas Chantal M. , Kutalik Zoltan , Lagou Vasiliki , Lind Penelope A. , Lorentzon Mattias , Lyytikäinen Leo-Pekka , Mangino Massimo , Metzendorf Christoph , Monroe Kristine R. , Pacolet Alexander , Pérusse Louis , Pool Rene , Richmond Rebecca C. , Rivera Natalia V. , Robiou-du-Pont Sebastien , Schraut Katharina E. , Schulz Christina-Alexandra , Stringham Heather M. , Tanaka Toshiko , Teumer Alexander , Turman Constance , van der Most Peter J. , Vanmunster Mathias , van Rooij Frank J. A. , van Vliet-Ostaptchouk Jana V. , Zhang Xiaoshuai , Zhao Jing-Hua , Zhao Wei , Balkhiyarova Zhanna , Balslev-Harder Marie N. , Baumeister Sebastian E. , Beilby John , Blangero John , Boomsma Dorret I. , Brage Soren , Braund Peter S. , Brody Jennifer A. , Bruinenberg Marcel , Ekelund Ulf , Liu Ching-Ti , Cole John W. , Collins Francis S. , Cupples L. Adrienne , Esko Tõnu , Enroth Stefan , Faul Jessica D. , Fernandez-Rhodes Lindsay , Fohner Alison E. , Franco Oscar H. , Galesloot Tessel E. , Gordon Scott D. , Grarup Niels , Hartman Catharina A. , Heiss Gerardo , Hui Jennie , Illig Thomas , Jago Russell , James Alan , Joshi Peter K. , Jung Taeyeong , Kähönen Mika , Kilpeläinen Tuomas O. , Koh Woon-Puay , Kolcic Ivana , Kraft Peter P. , Kuusisto Johanna , Launer Lenore J. , Li Aihua , Linneberg Allan , Luan Jian’an , Vidal Pedro Marques , Medland Sarah E. , Milaneschi Yuri , Moscati Arden , Musk Bill , Nelson Christopher P. , Nolte Ilja M. , Pedersen Nancy L. , Peters Annette , Peyser Patricia A. , Power Christine , Raitakari Olli T. , Reedik Mägi , Reiner Alex P. , Ridker Paul M. , Rudan Igor , Ryan Kathy , Sarzynski Mark A. , Scott Laura J. , Scott Robert A. , Sidney Stephen , Siggeirsdottir Kristin , Smith Albert V. , Smith Jennifer A. , Sonestedt Emily , Strøm Marin , Tai E. Shyong , Teo Koon K. , Thorand Barbara , Tönjes Anke , Tremblay Angelo , Uitterlinden Andre G. , Vangipurapu Jagadish , van Schoor Natasja , Völker Uwe , Willemsen Gonneke , Williams Kayleen , Wong Quenna , Xu Huichun , Young Kristin L. , Yuan Jian Min , Zillikens M. Carola , Zonderman Alan B. , Ameur Adam , Bandinelli Stefania , Bis Joshua C. , Boehnke Michael , Bouchard Claude , Chasman Daniel I. , Smith George Davey , de Geus Eco J. C. , Deldicque Louise , Dörr Marcus , Evans Michele K. , Ferrucci Luigi , Fornage Myriam , Fox Caroline , Garland Theodore , Gudnason Vilmundur , Gyllensten Ulf , Hansen Torben , Hayward Caroline , Horta Bernardo L. , Hyppönen Elina , Jarvelin Marjo-Riitta , Johnson W. Craig , Kardia Sharon L. R. , Kiemeney Lambertus A. , Laakso Markku , Langenberg Claudia , Lehtimäki Terho , Marchand Loic Le ,   Lifelines Cohort Study, Alizadeh Behrooz Z. , Boezen H. Marike , Franke Lude , Swertz Morris , Wijmenga Cisca , van der Harst Pim , Navis Gerjan , Rots Marianne , Wolffenbuttel Bruce H. R. , Magnusson Patrik K. E. , Martin Nicholas G. , Melbye Mads , Metspalu Andres , Meyre David , North Kari E. , Ohlsson Claes , Oldehinkel Albertine J. , Orho-Melander Marju , Pare Guillaume , Park Taesung , Pedersen Oluf , Penninx Brenda W. J. H. , Pers Tune H. , Polasek Ozren , Prokopenko Inga , Rotimi Charles N. , Samani Nilesh J. , Sim Xueling , Snieder Harold , Sørensen Thorkild I. A. , Spector Tim D. , Timpson Nicholas J. , van Dam Rob M. , van der Velde Nathalie , van Duijn Cornelia M. , Vollenweider Peter , Völzke Henry , Voortman Trudy , Waeber Gérard , Wareham Nicholas J. , Weir David R. , Wichmann Heinz-Erich , Wilson James F. , Hevener Andrea L. , Krook Anna , Zierath Juleen R. , Thomis Martine A. I. , Loos Ruth J. F. , Hoed Marcel den 
Published: September 2022

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.