Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness

Sara M. Willems; Daniel J. Wright; Felix R. Day; Katerina Trajanoska; Peter K. Joshi; John A. Morris; Amy M. Matteini; Fleur C. Garton; Niels Grarup; Nikolay Oskolkov; Anbupalam Thalamuthu; Massimo Mangino; Jun Liu; Ayse Demirkan; Monkol Lek; Liwen Xu; Guan Wang; Christopher Oldmeadow; Kyle J. Gaulton; Luca A. Lotta; Eri Miyamoto-Mikami; Manuel A. Rivas; Tom White; Po Ru Loh; Mette Aadahl; Najaf Amin; John R. Attia; Krista Austin; Beben Benyamin; Soren Brage; Yu Ching Cheng; Paweł Cięszczyk; Wim Derave; Karl Fredrik Eriksson; Nir Eynon; Allan Linneberg; Alejandro Lucia; Myosotis Massidda; Braxton D. Mitchell; Motohiko Miyachi; Haruka Murakami; Sandosh Padmanabhan; Ashutosh Pandey; Ioannis Papadimitriou; Deepak K. Rajpal; Craig Sale; Theresia M. Schnurr; Francesco Sessa; Nick Shrine; Martin D. Tobin; GEFOS Any-Type of Fracture Consortium; Yannis Pitsiladis; Noriyuki Fuku; Paul W. Franks; Kathryn N. North; Cornelia M. van Duijn; Karen A. Mather; Torben Hansen; Ola Hansson; Tim Spector; Joanne M. Murabito; J. Brent Richards; Fernando Rivadeneira; Claudia Langenberg; John R. B. Perry; Nick J. Wareham; Robert A. Scott

doi:10.1038/ncomms16015

Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness

Sara M. Willems, Daniel J. Wright, Felix R. Day, Katerina Trajanoska, Peter K. Joshi, John A. Morris, Amy M. Matteini, Fleur C. Garton, Niels Grarup, Nikolay Oskolkov, Anbupalam Thalamuthu, Massimo Mangino, Jun Liu, Ayse Demirkan, Monkol Lek, Liwen Xu, Guan Wang, Christopher Oldmeadow, Kyle J. Gaulton, Luca A. LottaEri Miyamoto-Mikami, Manuel A. Rivas, Tom White, Po Ru Loh, Mette Aadahl, Najaf Amin, John R. Attia, Krista Austin, Beben Benyamin, Soren Brage, Yu Ching Cheng, Paweł Cięszczyk, Wim Derave, Karl Fredrik Eriksson, Nir Eynon, Allan Linneberg, Alejandro Lucia, Myosotis Massidda, Braxton D. Mitchell, Motohiko Miyachi, Haruka Murakami, Sandosh Padmanabhan, Ashutosh Pandey, Ioannis Papadimitriou, Deepak K. Rajpal, Craig Sale, Theresia M. Schnurr, Francesco Sessa, Nick Shrine, Martin D. Tobin, GEFOS Any-Type of Fracture Consortium, Yannis Pitsiladis, Noriyuki Fuku, Paul W. Franks, Kathryn N. North, Cornelia M. van Duijn, Karen A. Mather, Torben Hansen, Ola Hansson, Tim Spector, Joanne M. Murabito, J. Brent Richards, Fernando Rivadeneira, Claudia Langenberg, John R. B. Perry, Nick J. Wareham^*, Robert A. Scott^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › peer-review

140 Citations (Scopus)

Abstract

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10⁻⁸) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

Original language	English
Article number	16015
Number of pages	12
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms16015
Publication status	Published - 12 Jul 2017

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Willems, S. M., Wright, D. J., Day, F. R., Trajanoska, K., Joshi, P. K., Morris, J. A., Matteini, A. M., Garton, F. C., Grarup, N., Oskolkov, N., Thalamuthu, A., Mangino, M., Liu, J., Demirkan, A., Lek, M., Xu, L., Wang, G., Oldmeadow, C., Gaulton, K. J., ... Scott, R. A. (2017). Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness. Nature Communications, 8, Article 16015. https://doi.org/10.1038/ncomms16015

@article{2993fd82b385417baccf150b9b4cfb9f,

title = "Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness",

abstract = "Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10−8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.",

author = "Willems, {Sara M.} and Wright, {Daniel J.} and Day, {Felix R.} and Katerina Trajanoska and Joshi, {Peter K.} and Morris, {John A.} and Matteini, {Amy M.} and Garton, {Fleur C.} and Niels Grarup and Nikolay Oskolkov and Anbupalam Thalamuthu and Massimo Mangino and Jun Liu and Ayse Demirkan and Monkol Lek and Liwen Xu and Guan Wang and Christopher Oldmeadow and Gaulton, {Kyle J.} and Lotta, {Luca A.} and Eri Miyamoto-Mikami and Rivas, {Manuel A.} and Tom White and Loh, {Po Ru} and Mette Aadahl and Najaf Amin and Attia, {John R.} and Krista Austin and Beben Benyamin and Soren Brage and Cheng, {Yu Ching} and Pawe{\l} Ci{\c e}szczyk and Wim Derave and Eriksson, {Karl Fredrik} and Nir Eynon and Allan Linneberg and Alejandro Lucia and Myosotis Massidda and Mitchell, {Braxton D.} and Motohiko Miyachi and Haruka Murakami and Sandosh Padmanabhan and Ashutosh Pandey and Ioannis Papadimitriou and Rajpal, {Deepak K.} and Craig Sale and Schnurr, {Theresia M.} and Francesco Sessa and Nick Shrine and Tobin, {Martin D.} and {GEFOS Any-Type of Fracture Consortium} and Yannis Pitsiladis and Noriyuki Fuku and Franks, {Paul W.} and North, {Kathryn N.} and {van Duijn}, {Cornelia M.} and Mather, {Karen A.} and Torben Hansen and Ola Hansson and Tim Spector and Murabito, {Joanne M.} and Richards, {J. Brent} and Fernando Rivadeneira and Claudia Langenberg and Perry, {John R. B.} and Wareham, {Nick J.} and Scott, {Robert A.}",

note = "Funding information: This research has been conducted using the UK Biobank Resource under application 12885. The Fenland Study is supported by the UK Medical Research Council (MRC) (MC_UU_12015/1; MC_UU_12015/2; MC_UU_12015/3). EPIC-Norfolk is supported by the MRC (G401527, G1000143) and Cancer Research UK (A8257). The HCS is gratefully supported by the University of Newcastle (Australia) and the Fairfax Family Foundation. Sydney MAS is supported by the Australian National Health and Medical Research Council (NHMRC), grants ID568969, ID350833 and ID109308. Sydney MAS DNA was extracted by Genetic Repositories Australia, funded by NHMRC Enabling Grant 401184. The GEFOS Study, used as controls for the US and Jamaican athletes, was supported in part by NIH grants U01 HG004436 and P30 DK072488, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). TwinsUK was funded by the Wellcome Trust (WT), MRC, and European Union. The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. SNP Genotyping was performed by The WT Sanger Institute and National Eye Institute via NIH/CIDR. M.McC is a WT Senior Investigator and receives support from WT 090532 and 098381. TW is the recipient of a studentship from MedImmune. Research by A. Lucia is supported by Fondo de Investigaciones Sanitarias and Fondos Feder (grant # PI15/0558). EM-M. was a recipient of a Grant-in-Aid for JSPS Fellow from the Japan Society for the Promotion of Science. This work was supported in part by grants from the Grant-in-Aid for Scientific Research (B) (15H03081 to NF) of the Japanese Ministry of Education, Culture, Sports, Science and Technology and by a grant-in-aid for scientific research (to M. Miyachi) from the Japanese Ministry of Health, Labor, and Welfare. This work was further supported by NIH grants R01 AR41398 and U24 AG051129. We gratefully acknowledge the contribution of all study participants and associated Research Teams. Publisher copyright: {\textcopyright} The Author(s) 2017",

year = "2017",

month = jul,

day = "12",

doi = "10.1038/ncomms16015",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Willems, SM, Wright, DJ, Day, FR, Trajanoska, K, Joshi, PK, Morris, JA, Matteini, AM, Garton, FC, Grarup, N, Oskolkov, N, Thalamuthu, A, Mangino, M, Liu, J, Demirkan, A, Lek, M, Xu, L, Wang, G, Oldmeadow, C, Gaulton, KJ, Lotta, LA, Miyamoto-Mikami, E, Rivas, MA, White, T, Loh, PR, Aadahl, M, Amin, N, Attia, JR, Austin, K, Benyamin, B, Brage, S, Cheng, YC, Cięszczyk, P, Derave, W, Eriksson, KF, Eynon, N, Linneberg, A, Lucia, A, Massidda, M, Mitchell, BD, Miyachi, M, Murakami, H, Padmanabhan, S, Pandey, A, Papadimitriou, I, Rajpal, DK, Sale, C, Schnurr, TM, Sessa, F, Shrine, N, Tobin, MD, GEFOS Any-Type of Fracture Consortium, Pitsiladis, Y, Fuku, N, Franks, PW, North, KN, van Duijn, CM, Mather, KA, Hansen, T, Hansson, O, Spector, T, Murabito, JM, Richards, JB, Rivadeneira, F, Langenberg, C, Perry, JRB, Wareham, NJ & Scott, RA 2017, 'Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness', Nature Communications, vol. 8, 16015. https://doi.org/10.1038/ncomms16015

TY - JOUR

T1 - Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness

AU - Willems, Sara M.

AU - Wright, Daniel J.

AU - Day, Felix R.

AU - Trajanoska, Katerina

AU - Joshi, Peter K.

AU - Morris, John A.

AU - Matteini, Amy M.

AU - Garton, Fleur C.

AU - Grarup, Niels

AU - Oskolkov, Nikolay

AU - Thalamuthu, Anbupalam

AU - Mangino, Massimo

AU - Liu, Jun

AU - Demirkan, Ayse

AU - Lek, Monkol

AU - Xu, Liwen

AU - Wang, Guan

AU - Oldmeadow, Christopher

AU - Gaulton, Kyle J.

AU - Lotta, Luca A.

AU - Miyamoto-Mikami, Eri

AU - Rivas, Manuel A.

AU - White, Tom

AU - Loh, Po Ru

AU - Aadahl, Mette

AU - Amin, Najaf

AU - Attia, John R.

AU - Austin, Krista

AU - Benyamin, Beben

AU - Brage, Soren

AU - Cheng, Yu Ching

AU - Cięszczyk, Paweł

AU - Derave, Wim

AU - Eriksson, Karl Fredrik

AU - Eynon, Nir

AU - Linneberg, Allan

AU - Lucia, Alejandro

AU - Massidda, Myosotis

AU - Mitchell, Braxton D.

AU - Miyachi, Motohiko

AU - Murakami, Haruka

AU - Padmanabhan, Sandosh

AU - Pandey, Ashutosh

AU - Papadimitriou, Ioannis

AU - Rajpal, Deepak K.

AU - Sale, Craig

AU - Schnurr, Theresia M.

AU - Sessa, Francesco

AU - Shrine, Nick

AU - Tobin, Martin D.

AU - GEFOS Any-Type of Fracture Consortium

AU - Pitsiladis, Yannis

AU - Fuku, Noriyuki

AU - Franks, Paul W.

AU - North, Kathryn N.

AU - van Duijn, Cornelia M.

AU - Mather, Karen A.

AU - Hansen, Torben

AU - Hansson, Ola

AU - Spector, Tim

AU - Murabito, Joanne M.

AU - Richards, J. Brent

AU - Rivadeneira, Fernando

AU - Langenberg, Claudia

AU - Perry, John R. B.

AU - Wareham, Nick J.

AU - Scott, Robert A.

N1 - Funding information: This research has been conducted using the UK Biobank Resource under application 12885. The Fenland Study is supported by the UK Medical Research Council (MRC) (MC_UU_12015/1; MC_UU_12015/2; MC_UU_12015/3). EPIC-Norfolk is supported by the MRC (G401527, G1000143) and Cancer Research UK (A8257). The HCS is gratefully supported by the University of Newcastle (Australia) and the Fairfax Family Foundation. Sydney MAS is supported by the Australian National Health and Medical Research Council (NHMRC), grants ID568969, ID350833 and ID109308. Sydney MAS DNA was extracted by Genetic Repositories Australia, funded by NHMRC Enabling Grant 401184. The GEFOS Study, used as controls for the US and Jamaican athletes, was supported in part by NIH grants U01 HG004436 and P30 DK072488, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). TwinsUK was funded by the Wellcome Trust (WT), MRC, and European Union. The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. SNP Genotyping was performed by The WT Sanger Institute and National Eye Institute via NIH/CIDR. M.McC is a WT Senior Investigator and receives support from WT 090532 and 098381. TW is the recipient of a studentship from MedImmune. Research by A. Lucia is supported by Fondo de Investigaciones Sanitarias and Fondos Feder (grant # PI15/0558). EM-M. was a recipient of a Grant-in-Aid for JSPS Fellow from the Japan Society for the Promotion of Science. This work was supported in part by grants from the Grant-in-Aid for Scientific Research (B) (15H03081 to NF) of the Japanese Ministry of Education, Culture, Sports, Science and Technology and by a grant-in-aid for scientific research (to M. Miyachi) from the Japanese Ministry of Health, Labor, and Welfare. This work was further supported by NIH grants R01 AR41398 and U24 AG051129. We gratefully acknowledge the contribution of all study participants and associated Research Teams. Publisher copyright: © The Author(s) 2017

PY - 2017/7/12

Y1 - 2017/7/12

N2 - Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10−8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

AB - Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10−8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85024482942&origin=resultslist&sort=plf-f&src=s&sid=c4811e9d02b32afc7497bf96c4af4688&sot=b&sdt=b&s=DOI%2810.1038%2Fncomms16015%29&sl=24&sessionSearchId=c4811e9d02b32afc7497bf96c4af4688&relpos=0

U2 - 10.1038/ncomms16015

DO - 10.1038/ncomms16015

M3 - Journal article

C2 - 29313844

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 16015

ER -

Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness

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