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

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, 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, D; McCarthy, MI; Pedersen, O; Khaw, K-T; Kiel, DP; 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

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

Accepted version

Peer-reviewed

Repository URI

https://www.repository.cam.ac.uk/handle/1810/264535

Repository DOI

https://doi.org/10.17863/CAM.9625

Files

Published version (397.87 KB)

Accepted version (272.48 KB) (Embargoed until: 2100-01-01)

Type

Article

Authors

Willems, SM

Wright, DJ

Day, FR

Trajanoska, K

Joshi, PK

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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.

Keywords

Actins, Adult, Aged, Cohort Studies, Female, Genetic Loci, Genetics, Population, Genome-Wide Association Study, Hand, Hand Strength, Humans, Male, Membrane Proteins, Middle Aged, Neoplasm Proteins, Nuclear Proteins, Polymorphism, Single Nucleotide, Repressor Proteins, Transforming Growth Factor alpha, United Kingdom, White People

Journal Title

Nature Communications

Journal ISSN

2041-1723
2041-1723

Volume Title

8

Publisher

Nature Publishing Group

Publisher DOI

https://doi.org/10.1038/ncomms16015

Rights

Attribution 4.0 International

Sponsorship

Medical Research Council (MC_UU_12015/1)
Medical Research Council (MC_UU_12015/2)
Medical Research Council (MC_UU_12015/3)
Medical Research Council (G1000143)
Cancer Research Uk (None)
Research into Ageing (RiA) (262)
Medical Research Council (G0401527)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0512-10135)
MRC (MC_PC_13048)
Department of Health (via National Institute for Health Research (NIHR)) (unknown)
National Institute for Health Research (NIHR) (NF-SI-0512-10114)
Medical Research Council (MR/N003284/1)
Cancer Research Uk (None)
TCC (None)
Medical Research Council (MC_U106179473)
Medical Research Council (G0401527/1)

This research has been conducted using the UK Biobank Resource. 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.

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