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 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; Søren  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; Ian Varley; Louise V.  Wain; Naomi R.  Wray; Cecilia M.  Lindgren; Daniel G.  MacArthur; Dawn M.  Waterworth; Mark I. McCarthy; Oluf Pedersen; Kay-Tee  Khaw; Douglas P. Kiel; 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 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, Søren 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, Ian Varley, Louise V. Wain, Naomi R. Wray, Cecilia M. Lindgren, Daniel G. MacArthur, Dawn M. Waterworth, Mark I. McCarthy, Oluf Pedersen, Kay-Tee Khaw, Douglas P. Kiel, 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

Research output: Contribution to journal › Article › peer-review

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 (Po5108) 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
Pages (from-to)	1-12
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms16015
Publication status	Published - 12 Jul 2017

Bibliographical note

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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Willems, S. M., Wright, D. J., Day, F. R., Trajanoska, K., Joshi, P. K., Morris, J. A., Matteini, A., 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, 1-12. Article 16015. https://doi.org/10.1038/ncomms16015

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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 (Po5108) 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 Amy Matteini 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 {A. Rivas}, Manuel and Tom White and Po-Ru Loh and Mette Aadahl and Najaf Amin and Attia, {John R.} and Krista Austin and Beben Benyamin and S{\o}ren Brage and Yu-Ching Cheng and Pawe{\l} Ci{\c e}szczyk and Wim Derave and Karl-Fredrik Eriksson 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 Ian Varley and Wain, {Louise V.} and Wray, {Naomi R.} and Lindgren, {Cecilia M.} and MacArthur, {Daniel G.} and Waterworth, {Dawn M.} and McCarthy, {Mark I.} and Oluf Pedersen and Kay-Tee Khaw and Kiel, {Douglas P.} 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 = "This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/",

year = "2017",

month = jul,

day = "12",

doi = "10.1038/ncomms16015",

language = "English",

volume = "8",

pages = "1--12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group UK",

}

Willems, SM, Wright, DJ, Day, FR, Trajanoska, K, Joshi, PK, Morris, JA, Matteini, A, 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, A. Rivas, M, White, T, Loh, P-R, Aadahl, M, Amin, N, Attia, JR, Austin, K, Benyamin, B, Brage, S, Cheng, Y-C, Cięszczyk, P, Derave, W, Eriksson, K-F, 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, Varley, I, Wain, LV, Wray, NR, Lindgren, CM, MacArthur, DG, Waterworth, DM, McCarthy, MI, Pedersen, O, Khaw, K-T, Kiel, DP, 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, pp. 1-12. 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

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 - A. Rivas, Manuel

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, Søren

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 - Varley, Ian

AU - Wain, Louise V.

AU - Wray, Naomi R.

AU - Lindgren, Cecilia M.

AU - MacArthur, Daniel G.

AU - Waterworth, Dawn M.

AU - McCarthy, Mark I.

AU - Pedersen, Oluf

AU - Khaw, Kay-Tee

AU - Kiel, Douglas P.

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 - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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 (Po5108) 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 (Po5108) 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.

U2 - 10.1038/ncomms16015

DO - 10.1038/ncomms16015

M3 - Article

SN - 2041-1723

VL - 8

SP - 1

EP - 12

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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