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; Asa Johansson; Anja Moltke Jorgensen; Marika A. Kaakinen; Robert Karlsson; Kathleen F. Kerr; Boram Kim; Chantal M. Koolhaas; Zoltan Kutalik; Vasiliki Lagou; Peter J. Van der Most; Jana V. Van Vliet-Ostaptchouk; Jing-Hua Zhao; Wei Zhao; Marcel Bruinenberg; Catharina A. Hartman; Ilja M. Nolte; Albert Smith; Albertine J. Oldehinkel; Brenda W. J. H. Penninx; Harold Snieder

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, Asa Johansson, Anja Moltke Jorgensen, Marika A. Kaakinen, Robert Karlsson, Kathleen F. Kerr, Boram Kim, Chantal M. Koolhaas, Zoltan Kutalik, Vasiliki Lagou, Peter J. Van der Most, Jana V. Van Vliet-Ostaptchouk, Jing-Hua Zhao, Wei Zhao, Marcel Bruinenberg, Catharina A. Hartman, Ilja M. Nolte, Albert Smith, Albertine J. Oldehinkel, Brenda W. J. H. Penninx, Harold Snieder

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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.

Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.

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

Keywords

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

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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., ... Snieder, H. (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.Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.",

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 Asa Johansson and Jorgensen, {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 {Van der Most}, {Peter J.} and {Van Vliet-Ostaptchouk}, {Jana V.} and Jing-Hua Zhao and Wei Zhao and Marcel Bruinenberg and Hartman, {Catharina A.} and Nolte, {Ilja M.} and Albert Smith and Oldehinkel, {Albertine J.} and Penninx, {Brenda W. J. H.} and Harold Snieder",

note = "{\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",

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number = "9",

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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, A, Jorgensen, AM, Kaakinen, MA, Karlsson, R, Kerr, KF, Kim, B, Koolhaas, CM, Kutalik, Z, Lagou, V, Van der Most, PJ , Van Vliet-Ostaptchouk, JV, Zhao, J-H, Zhao, W, Bruinenberg, M, Hartman, CA , Nolte, IM, Smith, A, Oldehinkel, AJ, Penninx, BWJH & Snieder, H 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 - 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, Asa

AU - Jorgensen, 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 - Van der Most, Peter J.

AU - Van Vliet-Ostaptchouk, Jana V.

AU - Zhao, Jing-Hua

AU - Zhao, Wei

AU - Bruinenberg, Marcel

AU - Hartman, Catharina A.

AU - Nolte, Ilja M.

AU - Smith, Albert

AU - Oldehinkel, Albertine J.

AU - Penninx, Brenda W. J. H.

AU - Snieder, Harold

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.Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.

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.Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.

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

SN - 1061-4036

VL - 54

SP - 1332

EP - 1344

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -