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

Research output: Contribution to journalArticlepeer-review

LifeLines Cohort Study

Original languageEnglish
Pages (from-to)1332-1344
Number of pages13
JournalNature genetics
Issue number9
Accepted/In press2022
PublishedSep 2022

Bibliographical note

Funding Information: T.S.A. is supported by the Steno Diabetes Center Copenhagen, Copenhagen, Denmark and the Novo Nordisk Foundation Grant NNF18OC0052457. J.W.C. was supported by grants from the National Institutes of Health (NIH) (R01-NS100178; R01-NS105150), the US Department of Veterans Affairs and the American Heart Association (AHA) (15GPSPG23770000; 17IBDG33700328). B.F. was supported by the Oak Foundation. T.O.K. was supported by the Novo Nordisk Foundation (grant numbers NNF17OC0026848 and NNF18CC0034900). N.G.M. is funded by a National Health and Medical Research Council (NHMRC) Investigator Grant (APP1172990). S.E.M. is funded by NHMRC Investigator Grant (APP1172917). D.M. is supported by a Canada Research Chair in Genetics of Obesity. R.C.R. is a de Pass Vice Chancellor's Research Fellow at the University of Bristol. S.R.-d.-P was supported by the Heart and Stroke Foundation of Ontario (grant number NA 7293). N.J.S. holds a National Institute for Health and Care Research (NIHR) Senior Investigator award. N.J.T. is a Wellcome Trust (WT) Investigator (202802/Z/16/Z), is the principal investigator of the Avon Longitudinal Study of Parents and Children (Medical Research Council (MRC) & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-2001), the MRC Integrative Epidemiology Unit (MC_UU_00011) and works within the Cancer Research UK Integrative Cancer Epidemiology Programme (C18281/A19169). X.Z. is supported by China Scholarship Council 201406220101. T.P. is supported by the Bio-Synergy Research Project (2013M3A9C4078158) of the Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea. S.S. is supported by the Swedish Research Council (grant numbers 2016-06264, 2018-05946 and 2018-05498). J.W.C. was partially supported by an AHA-Bayer Discovery Grant (grant 17IBDG33700328), the AHA Cardiovascular Genome–Phenome Study (grant-15GPSPG23770000), NIH (grants R01-NS114045, R01-NS100178, R01-NS105150), and the US Department of Veterans Affairs. H.X. was supported by AHA grant 19CDA34760258 and NIH grants R01-NS114045, R01-NS100178 and R01-NS105150. K.E.N. is funded by AHA grants 13GRNT16490017 and 15GRNT25880008, and by NIH grants R01DK089256, R01DK101855, R01HD057194, R01DK122503, 01HG010297, R01HL142302, R01HL143885 and R01HG009974. L.F.-R. is supported by an AHA grant (13PRE16100015). C.P.N. is funded by the British Heart Foundation (SP/16/4/32697). L.M.H., C.P.N., P.S.B. and N.J.S. are supported by the NIHR Leicester Cardiovascular Biomedical Research Centre (BRC-1215-20010). T.G. Jr and D.H. were supported by US National Science Foundation grant IOS-2038528. R.J.F.L. is supported by the NIH (R01DK110113, R01DK075787, R01DK107786, R01HL142302, R01HG010297, R01DK124097, R01HL151152). M.d.H. is a fellow of the Swedish Heart–Lung Foundation (20170872, 20200781) and a Kjell and Märta Beijer Foundation researcher. He is further supported by project grants from the Swedish Heart–Lung Foundation (20140543, 20170678, 20180706, 20200602) and the Swedish Research Council (2015-03657, 2019-01417). Publisher Copyright: © 2022, The Author(s).

King's Authors


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.

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