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

LifeLines Cohort Study; Katharina E Schraut; Peter K Joshi; Igor Rudan; Caroline Hayward; James F Wilson

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

LifeLines Cohort Study, Katharina E Schraut, Peter K Joshi, Igor Rudan, Caroline Hayward, James F Wilson

Research output: Contribution to journal › Article › 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 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 language	English
Article number	1332–1344
Pages (from-to)	1332-1344
Number of pages	25
Journal	Nature Genetics
Volume	54
Issue number	9
Early online date	7 Sep 2022
DOIs	https://doi.org/10.1038/s41588-022-01165-1
Publication status	Published - 7 Sep 2022

Keywords

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

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10.1038/s41588-022-01165-1Licence: Creative Commons: Attribution (CC-BY)

Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease preventionFinal published version, 6.78 MBLicence: Creative Commons: Attribution (CC-BY)

Cite this

@article{f19926d19ca7420b9396258ab18d3a33,

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.",

keywords = "Actinin/genetics, Cross-Sectional Studies, Exercise/physiology, Genome-Wide Association Study, Humans, Leisure Activities, Sedentary Behavior",

author = "{LifeLines Cohort Study} and 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 Leo-Pekka Lyytik{\"a}inen 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 Christina-Alexandra Schulz 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 Jing-Hua Zhao 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 Ching-Ti Liu and Cole, {John W} and Collins, {Francis S} and Cupples, {L Adrienne} and T{\~o}nu Esko and Stefan Enroth and Faul, {Jessica D} and Lindsay Fernandez-Rhodes and Fohner, {Alison E} and Franco, {Oscar H} and Galesloot, {Tessel E} and Gordon, {Scott D} and Niels Grarup and Hartman, {Catharina A} and Gerardo Heiss and Jennie Hui and Thomas Illig and Russell Jago and Alan James and Joshi, {Peter K} and Taeyeong Jung and Mika K{\"a}h{\"o}nen and Kilpel{\"a}inen, {Tuomas O} and Woon-Puay Koh and Ivana Kolcic and Kraft, {Peter P} and Johanna Kuusisto and Launer, {Lenore J} and Aihua Li and Allan Linneberg and Jian'an Luan and Vidal, {Pedro Marques} and Medland, {Sarah E} and Yuri Milaneschi and Arden Moscati and Bill Musk and Nelson, {Christopher P} and Nolte, {Ilja M} and Pedersen, {Nancy L} and Annette Peters and Peyser, {Patricia A} and Christine Power and Raitakari, {Olli T} and M{\"a}gi Reedik and Reiner, {Alex P} and Ridker, {Paul M} and Igor Rudan and Kathy Ryan and Sarzynski, {Mark A} and Scott, {Laura J} and Scott, {Robert A} and Stephen Sidney and Kristin Siggeirsdottir and Smith, {Albert V} and Smith, {Jennifer A} and Emily Sonestedt and Marin Str{\o}m and Tai, {E Shyong} and Teo, {Koon K} and Barbara Thorand and Anke T{\"o}njes and Angelo Tremblay and Uitterlinden, {Andre G} and Jagadish Vangipurapu and {van Schoor}, Natasja and Uwe V{\"o}lker and Gonneke Willemsen and Kayleen Williams and Quenna Wong and Huichun Xu and Young, {Kristin L} and Yuan, {Jian Min} and Zillikens, {M Carola} and Zonderman, {Alan B} and Adam Ameur and Stefania Bandinelli and Bis, {Joshua C} and Michael Boehnke and Claude Bouchard and Chasman, {Daniel I} and Smith, {George Davey} and {de Geus}, {Eco J C} and Louise Deldicque and Marcus D{\"o}rr and Evans, {Michele K} and Luigi Ferrucci and Myriam Fornage and Caroline Fox and Theodore Garland and Vilmundur Gudnason and Ulf Gyllensten and Torben Hansen and Caroline Hayward and Horta, {Bernardo L} and Elina Hypp{\"o}nen and Marjo-Riitta Jarvelin and Johnson, {W Craig} and Kardia, {Sharon L R} and Kiemeney, {Lambertus A} and Markku Laakso and Claudia Langenberg and Terho Lehtim{\"a}ki and Marchand, {Loic Le} and Magnusson, {Patrik K E} and Martin, {Nicholas G} and Mads Melbye and Andres Metspalu and David Meyre and North, {Kari E} and Claes Ohlsson and Oldehinkel, {Albertine J} and Marju Orho-Melander and Guillaume Pare and Taesung Park and Oluf Pedersen and Penninx, {Brenda W J H} and Pers, {Tune H} and Ozren Polasek and Inga Prokopenko and Rotimi, {Charles N} and Samani, {Nilesh J} and Xueling Sim and Harold Snieder and S{\o}rensen, {Thorkild I A} and Spector, {Tim D} and Timpson, {Nicholas J} and {van Dam}, {Rob M} and {van der Velde}, Nathalie and {van Duijn}, {Cornelia M} and Peter Vollenweider and Henry V{\"o}lzke and Trudy Voortman and G{\'e}rard Waeber and Wareham, {Nicholas J} and Weir, {David R} and Heinz-Erich Wichmann and Wilson, {James F} and Hevener, {Andrea L} and Anna Krook and Zierath, {Juleen R} and Thomis, {Martine A I} and Loos, {Ruth J F} and Hoed, {Marcel den}",

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,

day = "7",

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

language = "English",

volume = "54",

pages = "1332--1344",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "9",

}

TY - JOUR

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

AU - LifeLines Cohort Study

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

AU - Bandinelli, Stefania

AU - Bis, Joshua C

AU - Boehnke, Michael

AU - Bouchard, Claude

AU - Chasman, Daniel I

AU - Smith, George Davey

AU - de Geus, Eco J C

AU - Deldicque, Louise

AU - Dörr, Marcus

AU - Evans, Michele K

AU - Ferrucci, Luigi

AU - Fornage, Myriam

AU - Fox, Caroline

AU - Garland, Theodore

AU - Gudnason, Vilmundur

AU - Gyllensten, Ulf

AU - Hansen, Torben

AU - Hayward, Caroline

AU - Horta, Bernardo L

AU - Hyppönen, Elina

AU - Jarvelin, Marjo-Riitta

AU - Johnson, W Craig

AU - Kardia, Sharon L R

AU - Kiemeney, Lambertus A

AU - Laakso, Markku

AU - Langenberg, Claudia

AU - Lehtimäki, Terho

AU - Marchand, Loic Le

AU - Magnusson, Patrik K E

AU - Martin, Nicholas G

AU - Melbye, Mads

AU - Metspalu, Andres

AU - Meyre, David

AU - North, Kari E

AU - Ohlsson, Claes

AU - Oldehinkel, Albertine J

AU - Orho-Melander, Marju

AU - Pare, Guillaume

AU - Park, Taesung

AU - Pedersen, Oluf

AU - Penninx, Brenda W J H

AU - Pers, Tune H

AU - Polasek, Ozren

AU - Prokopenko, Inga

AU - Rotimi, Charles N

AU - Samani, Nilesh J

AU - Sim, Xueling

AU - Snieder, Harold

AU - Sørensen, Thorkild I A

AU - Spector, Tim D

AU - Timpson, Nicholas J

AU - van Dam, Rob M

AU - van der Velde, Nathalie

AU - van Duijn, Cornelia M

AU - Vollenweider, Peter

AU - Völzke, Henry

AU - Voortman, Trudy

AU - Waeber, Gérard

AU - Wareham, Nicholas J

AU - Weir, David R

AU - Wichmann, Heinz-Erich

AU - Wilson, James F

AU - Hevener, Andrea L

AU - Krook, Anna

AU - Zierath, Juleen R

AU - Thomis, Martine A I

AU - Loos, Ruth J F

AU - Hoed, Marcel den

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 - 2022/9/7

Y1 - 2022/9/7

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.

KW - Actinin/genetics

KW - Cross-Sectional Studies

KW - Exercise/physiology

KW - Genome-Wide Association Study

KW - Humans

KW - Leisure Activities

KW - Sedentary Behavior

U2 - 10.1038/s41588-022-01165-1

DO - 10.1038/s41588-022-01165-1

M3 - Article

C2 - 36071172

VL - 54

SP - 1332

EP - 1344

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 9

M1 - 1332–1344

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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