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

Lifelines cohort study; Zhe Wang; Andrew Emmerich; 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 Feenstra; Mary 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; Mattias Lorentzon; Leo Pekka Lyytikäinen; Massimo Mangino; Christoph Metzendorf; Kristine R. Monroe; Alexander Pacolet; Louis Pérusse; Mika Kähönen; Johanna Kuusisto; Terho Lehtimäki

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, Zhe Wang, Andrew Emmerich, 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, Mattias Lorentzon, Leo Pekka Lyytikäinen, Massimo Mangino, Christoph Metzendorf, Kristine R. Monroe, Alexander Pacolet, Louis Pérusse, Mika Kähönen, Johanna Kuusisto, Terho Lehtimäki

Tutkimustuotos: Artikkeli › Scientific › vertaisarvioitu

Abstrakti

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.

Alkuperäiskieli	Englanti
Sivut	1332-1344
Sivumäärä	13
Julkaisu	Nature Genetics
Vuosikerta	54
DOI - pysyväislinkit	https://doi.org/10.1038/s41588-022-01165-1
Tila	Julkaistu - 2022
OKM-julkaisutyyppi	A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

Julkaisufoorumi-taso

Jufo-taso 3

!!ASJC Scopus subject areas

Genetics

Pääsy asiakirjaan

10.1038/s41588-022-01165-1Lisenssi: CC BY

s41588-022-01165-1Final published version, 6,8 MBLisenssi: CC BY

https://urn.fi/URN:NBN:fi:tuni-202211248620Lisenssi: CC BY

Siteeraa tätä

Lifelines cohort study, Wang, Z., Emmerich, A., Pillon, N. J., Moore, T., Hemerich, D., Cornelis, M. C., Mazzaferro, E., Broos, S., Ahluwalia, T. S., Bartz, T. M., Bentley, A. R., Bielak, L. F., Chong, M., Chu, A. Y., Berry, D., Dorajoo, R., Dueker, N. D., Kasbohm, E., ... Lehtimäki, T. (2022). Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention. Nature Genetics, 54, 1332-1344. https://doi.org/10.1038/s41588-022-01165-1

@article{1195caec64154cca98179c12d4ad5082,

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 = "{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 Lyytik{\"a}inen, {Leo Pekka} and Massimo Mangino and Christoph Metzendorf and Monroe, {Kristine R.} and Alexander Pacolet and Louis P{\'e}russe and Mika K{\"a}h{\"o}nen and Johanna Kuusisto and Terho Lehtim{\"a}ki",

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",

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

language = "English",

volume = "54",

pages = "1332--1344",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

}

Lifelines cohort study, Wang, Z, Emmerich, A, Pillon, NJ, Moore, T, Hemerich, D, Cornelis, MC, Mazzaferro, E, Broos, S, Ahluwalia, TS, Bartz, TM, Bentley, AR, Bielak, LF, Chong, M, Chu, AY, Berry, D, Dorajoo, R, Dueker, ND, Kasbohm, E, Feenstra, B, Feitosa, MF, Gieger, C, Graff, M, Hall, LM, Haller, T, Hartwig, FP, Hillis, DA, Huikari, V, Heard-Costa, N, Holzapfel, C, Jackson, AU, Johansson, Å, Jørgensen, AM, Kaakinen, MA, Karlsson, R, Kerr, KF, Kim, B, Koolhaas, CM, Kutalik, Z, Lagou, V, Lind, PA, Lorentzon, M, Lyytikäinen, LP, Mangino, M, Metzendorf, C, Monroe, KR, Pacolet, A, Pérusse, L, Kähönen, M, Kuusisto, J & Lehtimäki, T 2022, 'Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention', Nature Genetics, Vuosikerta 54, Sivut 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 - 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 - Kähönen, Mika

AU - Kuusisto, Johanna

AU - Lehtimäki, Terho

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

Y1 - 2022

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.

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

ER -

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

Abstrakti

Julkaisufoorumi-taso

!!ASJC Scopus subject areas

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