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

Zhe Wang; Andrew Emmerich; Nicolas J. Pillon; Rene Pool; Dorret I. Boomsma; Yuri Milaneschi; Gonneke Willemsen; Eco J.C. de Geus; LifeLines Cohort Study

doi:10.1038/s41588-022-01165-1

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

Zhe Wang^*
, Andrew Emmerich
, Nicolas J. Pillon
, Rene Pool
, Dorret I. Boomsma
, Yuri Milaneschi
, Gonneke Willemsen
, Eco J.C. de Geus
, LifeLines Cohort Study

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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_A 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 language	English
Pages (from-to)	1332-1344
Number of pages	13
Journal	Nature genetics
Volume	54
Issue number	9
Early online date	7 Sept 2022
DOIs	https://doi.org/10.1038/s41588-022-01165-1
Publication status	Published - Sept 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).

Funding

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).

Funders	Funder number
Canada Research Chair in Genetics of Obesity
National Research Foundation of Korea
Medical Research Council
Ministry of Science, ICT and Future Planning
Kjell och Märta Beijers Stiftelse
Integrative Cancer Epidemiology Programme
U.S. Department of Veterans Affairs
Steno Diabetes Center Copenhagen
National Health and Medical Research Council	APP1172917, APP1172990
Vetenskapsrådet	2018-05946, 2018-05498, 2016-06264
Hjärt-Lungfonden	20140543, 20200602, 20170678, 2019-01417, 2015-03657, 20180706
China Scholarship Council	201406220101, 2013M3A9C4078158
National Cancer Institute	UM1CA182876
National Science Foundation	2038528, R01HG010297, R01DK110113, R01HL151152, IOS-2038528, R01DK107786, R01DK075787, R01DK124097
Heart and Stroke Foundation of Canada	NA 7293
AHA-Bayer	R01HD057194, R01HL142302, 13PRE16100015, R01DK089256, 13GRNT16490017, 15GRNT25880008, 19CDA34760258, R01DK122503, R01HG009974, R01DK101855, R01-NS114045, R01HL143885, 01HG010297
NIHR Leicester Cardiovascular Biomedical Research Centre	BRC-1215-20010
National Heart, Lung, and Blood Institute	R01HL149683, R01HL105756
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK062370, P30DK020541
University of Bristol NIHR Biomedical Research Centre	BRC-1215-2001, MC_UU_00011
National Institutes of Health	R01-NS100178, R01-NS105150
Virginia Marine Resources Commission	WT 217065/Z/19/Z
American Heart Association	17IBDG33700328, 15GPSPG23770000
National Institute on Aging	U01AG070959
Novo Nordisk Fonden	NNF18OC0052457
Wellcome Trust	202802, 217065, 202802/Z/16/Z
Oak Foundation	NNF17OC0026848, NNF18CC0034900
British Heart Foundation	SP/16/4/32697
Cancer Research UK	C18281/A19169

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Wang, Z., Emmerich, A., Pillon, N. J., Pool, R., Boomsma, D. I., Milaneschi, Y., Willemsen, G., de Geus, E. J. C., & LifeLines Cohort Study (2022). Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention. Nature genetics, 54(9), 1332-1344. https://doi.org/10.1038/s41588-022-01165-1

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

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 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.",

author = "Zhe Wang and Andrew Emmerich and Pillon, \{Nicolas J.\} and Tim Moore and Daiane Hemerich and Cornelis, \{Marilyn C.\} and Eugenia Mazzaferro and Siacia Broos and Ahluwalia, \{Tarunveer S.\} and Bartz, \{Traci M.\} and Bentley, \{Amy R.\} and Bielak, \{Lawrence F.\} and Mike Chong and Chu, \{Audrey Y.\} and Diane Berry and Rajkumar Dorajoo and Dueker, \{Nicole D.\} and Elisa Kasbohm and Bjarke Feenstra and Feitosa, \{Mary F.\} and Christian Gieger and Mariaelisa Graff and Hall, \{Leanne M.\} and Toomas Haller and Hartwig, \{Fernando P.\} and Hillis, \{David A.\} and Ville Huikari and Nancy Heard-Costa and Christina Holzapfel and Jackson, \{Anne U.\} and {\AA}sa Johansson and J{\o}rgensen, \{Anja Moltke\} and Kaakinen, \{Marika A.\} and Robert Karlsson and Kerr, \{Kathleen F.\} and Boram Kim and Koolhaas, \{Chantal M.\} and Zoltan Kutalik and Vasiliki Lagou and Lind, \{Penelope A.\} and Mattias Lorentzon and Lyytik{\"a}inen, \{Leo Pekka\} and Massimo Mangino and Christoph Metzendorf and Monroe, \{Kristine R.\} and Alexander Pacolet and Louis P{\'e}russe and Rene Pool and Richmond, \{Rebecca C.\} and Rivera, \{Natalia V.\} and Sebastien Robiou-du-Pont and Schraut, \{Katharina E.\} and Schulz, \{Christina Alexandra\} and Stringham, \{Heather M.\} and Toshiko Tanaka and Alexander Teumer and Constance Turman and \{van der Most\}, \{Peter J.\} and Mathias Vanmunster and \{van Rooij\}, \{Frank J.A.\} and \{van Vliet-Ostaptchouk\}, \{Jana V.\} and Xiaoshuai Zhang and Zhao, \{Jing Hua\} and Wei Zhao and Zhanna Balkhiyarova and Balslev-Harder, \{Marie N.\} and Baumeister, \{Sebastian E.\} and John Beilby and John Blangero and Boomsma, \{Dorret I.\} and Soren Brage and Braund, \{Peter S.\} and Brody, \{Jennifer A.\} and Marcel Bruinenberg and Ulf Ekelund and Liu, \{Ching Ti\} and Cole, \{John W.\} and Collins, \{Francis S.\} and Cupples, \{L. 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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 M{\"a}rta 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: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = sep,

doi = "10.1038/s41588-022-01165-1",

language = "English",

volume = "54",

pages = "1332--1344",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "9",

}

Wang, Z, Emmerich, A, Pillon, NJ, Pool, R , Boomsma, DI, Milaneschi, Y, Willemsen, G, de Geus, EJC & LifeLines Cohort Study 2022, 'Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention', Nature genetics, vol. 54, no. 9, pp. 1332-1344. https://doi.org/10.1038/s41588-022-01165-1

TY - JOUR

T1 - Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention

AU - Wang, Zhe

AU - Emmerich, Andrew

AU - Pillon, Nicolas J.

AU - Moore, Tim

AU - Hemerich, Daiane

AU - Cornelis, Marilyn C.

AU - Mazzaferro, Eugenia

AU - Broos, Siacia

AU - Ahluwalia, Tarunveer S.

AU - Bartz, Traci M.

AU - Bentley, Amy R.

AU - Bielak, Lawrence F.

AU - Chong, Mike

AU - Chu, Audrey Y.

AU - Berry, Diane

AU - Dorajoo, Rajkumar

AU - Dueker, Nicole D.

AU - Kasbohm, Elisa

AU - Feenstra, Bjarke

AU - Feitosa, Mary F.

AU - Gieger, Christian

AU - Graff, Mariaelisa

AU - Hall, Leanne M.

AU - Haller, Toomas

AU - Hartwig, Fernando P.

AU - Hillis, David A.

AU - Huikari, Ville

AU - Heard-Costa, Nancy

AU - Holzapfel, Christina

AU - Jackson, Anne U.

AU - Johansson, Åsa

AU - Jørgensen, Anja Moltke

AU - Kaakinen, Marika A.

AU - Karlsson, Robert

AU - Kerr, Kathleen F.

AU - Kim, Boram

AU - Koolhaas, Chantal M.

AU - Kutalik, Zoltan

AU - Lagou, Vasiliki

AU - Lind, Penelope A.

AU - Lorentzon, Mattias

AU - Lyytikäinen, Leo Pekka

AU - Mangino, Massimo

AU - Metzendorf, Christoph

AU - Monroe, Kristine R.

AU - Pacolet, Alexander

AU - Pérusse, Louis

AU - Pool, Rene

AU - Richmond, Rebecca C.

AU - Rivera, Natalia V.

AU - Robiou-du-Pont, Sebastien

AU - Schraut, Katharina E.

AU - Schulz, Christina Alexandra

AU - Stringham, Heather M.

AU - Tanaka, Toshiko

AU - Teumer, Alexander

AU - Turman, Constance

AU - van der Most, Peter J.

AU - Vanmunster, Mathias

AU - van Rooij, Frank J.A.

AU - van Vliet-Ostaptchouk, Jana V.

AU - Zhang, Xiaoshuai

AU - Zhao, Jing Hua

AU - Zhao, Wei

AU - Balkhiyarova, Zhanna

AU - Balslev-Harder, Marie N.

AU - Baumeister, Sebastian E.

AU - Beilby, John

AU - Blangero, John

AU - Boomsma, Dorret I.

AU - Brage, Soren

AU - Braund, Peter S.

AU - Brody, Jennifer A.

AU - Bruinenberg, Marcel

AU - Ekelund, Ulf

AU - Liu, Ching Ti

AU - Cole, John W.

AU - Collins, Francis S.

AU - Cupples, L. Adrienne

AU - Esko, Tõnu

AU - Enroth, Stefan

AU - Faul, Jessica D.

AU - Fernandez-Rhodes, Lindsay

AU - Fohner, Alison E.

AU - Franco, Oscar H.

AU - Galesloot, Tessel E.

AU - Gordon, Scott D.

AU - Grarup, Niels

AU - Hartman, Catharina A.

AU - Heiss, Gerardo

AU - Hui, Jennie

AU - Illig, Thomas

AU - Jago, Russell

AU - James, Alan

AU - Joshi, Peter K.

AU - Jung, Taeyeong

AU - Kähönen, Mika

AU - Kilpeläinen, Tuomas O.

AU - Koh, Woon Puay

AU - Kolcic, Ivana

AU - Kraft, Peter P.

AU - Kuusisto, Johanna

AU - Launer, Lenore J.

AU - Li, Aihua

AU - Linneberg, Allan

AU - Luan, Jian’an

AU - Vidal, Pedro Marques

AU - Medland, Sarah E.

AU - Milaneschi, Yuri

AU - Moscati, Arden

AU - Musk, Bill

AU - Nelson, Christopher P.

AU - Nolte, Ilja M.

AU - Pedersen, Nancy L.

AU - Peters, Annette

AU - Peyser, Patricia A.

AU - Power, Christine

AU - Raitakari, Olli T.

AU - Reedik, Mägi

AU - Reiner, Alex P.

AU - Ridker, Paul M.

AU - Rudan, Igor

AU - Ryan, Kathy

AU - Sarzynski, Mark A.

AU - Scott, Laura J.

AU - Scott, Robert A.

AU - Sidney, Stephen

AU - Siggeirsdottir, Kristin

AU - Smith, Albert V.

AU - Smith, Jennifer A.

AU - Sonestedt, Emily

AU - Strøm, Marin

AU - Tai, E. Shyong

AU - Teo, Koon K.

AU - Thorand, Barbara

AU - Tönjes, Anke

AU - Tremblay, Angelo

AU - Uitterlinden, Andre G.

AU - Vangipurapu, Jagadish

AU - van Schoor, Natasja

AU - Völker, Uwe

AU - Willemsen, Gonneke

AU - Williams, Kayleen

AU - Wong, Quenna

AU - Xu, Huichun

AU - Young, Kristin L.

AU - Yuan, Jian Min

AU - Zillikens, M. Carola

AU - Zonderman, Alan B.

AU - Ameur, Adam

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AU - Magnusson, Patrik K.E.

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AU - LifeLines Cohort Study

N1 - 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).

PY - 2022/9

Y1 - 2022/9

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85137511928

UR - https://www.scopus.com/pages/publications/85137511928#tab=citedBy

U2 - 10.1038/s41588-022-01165-1

DO - 10.1038/s41588-022-01165-1

M3 - Article

C2 - 36071172

AN - SCOPUS:85137511928

SN - 1061-4036

VL - 54

SP - 1332

EP - 1344

JO - Nature genetics

JF - Nature genetics

IS - 9

ER -

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

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