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

GEFOS Anytype of Fracture Consortium

doi:10.1038/ncomms16015

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

GEFOS Anytype of Fracture Consortium

Bar-Ilan University - Azrieli Faculty of Medicine

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

146 Scopus citations

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
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms16015
State	Published - 12 Jul 2017

Bibliographical note

Publisher Copyright:
© The Author(s) 2017.

Funding

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 Med-Immune. 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.

Funders	Funder number
Baltimore Geriatrics Research
CIDR	098381, WT 090532
Fairfax Family Foundation
Fondo de Investigaciones Sanitarias and Fondos Feder	PI15/0558
WT Sanger Institute
National Institutes of Health	P30 DK072488
National Human Genome Research Institute	U01HG004436
National Eye Institute
U.S. Department of Veterans Affairs
Wellcome Trust
Medical Research Council	G1000143, MC-UU-12015/1, MC-UU-12015/2, MC-UU-12015/3, G401527
National Institute for Health and Care Research
Cancer Research UK	A8257
King's College London
European Commission
National Health and Medical Research Council	ID568969, ID350833, ID109308, 401184
Japan Society for the Promotion of Science	15H03081
Ministry of Education, Culture, Sports, Science and Technology
University of Newcastle Australia
Ministry of Health, Labour and Welfare	U24 AG051129, R01 AR41398
Guy's and St Thomas' NHS Foundation Trust
Novo Nordisk Fonden

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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 (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 = "{GEFOS Anytype of Fracture Consortium} and 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 S{\o}ren Brage and Cheng, {Yu Ching} and Pawe{\l} Ciȩszczyk 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 David Karasik",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2017.",

year = "2017",

month = jul,

day = "12",

doi = "10.1038/ncomms16015",

language = "אנגלית",

volume = "8",

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AU - GEFOS Anytype of Fracture Consortium

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, Søren

AU - Cheng, Yu Ching

AU - Ciȩszczyk, 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 - Karasik, David

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.

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JO - Nature Communications

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

Abstract

Bibliographical note

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