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.2017 Jul 12:8:16015.
doi: 10.1038/ncomms16015.

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

Sara M Willems  1Daniel J Wright  1Felix R Day  1Katerina Trajanoska  2  3Peter K Joshi  4John A Morris  5  6Amy M Matteini  7Fleur C Garton  8Niels Grarup  9Nikolay Oskolkov  10Anbupalam Thalamuthu  11Massimo Mangino  12  13Jun Liu  3Ayse Demirkan  3  14Monkol Lek  15  16Liwen Xu  15  16Guan Wang  17Christopher Oldmeadow  18Kyle J Gaulton  19Luca A Lotta  1Eri Miyamoto-Mikami  20  21Manuel A Rivas  22  23Tom White  1Po-Ru Loh  23  24Mette Aadahl  25Najaf Amin  3John R Attia  18  26  27Krista Austin  17Beben Benyamin  8  28Søren Brage  1Yu-Ching Cheng  29Paweł Cięszczyk  30Wim Derave  31Karl-Fredrik Eriksson  10Nir Eynon  32  33Allan Linneberg  25  34  35Alejandro Lucia  36  37Myosotis Massidda  38Braxton D Mitchell  29  39Motohiko Miyachi  40Haruka Murakami  40Sandosh Padmanabhan  41Ashutosh Pandey  42Ioannis Papadimitriou  32Deepak K Rajpal  42Craig Sale  43Theresia M Schnurr  9Francesco Sessa  44Nick Shrine  45  46Martin D Tobin  45  46Ian Varley  43Louise V Wain  45  46Naomi R Wray  8  28Cecilia M Lindgren  23  47  48Daniel G MacArthur  15  23Dawn M Waterworth  42Mark I McCarthy  48  49  50Oluf Pedersen  9Kay-Tee Khaw  51Douglas P Kiel  16  52  53GEFOS Any-Type of Fracture ConsortiumYannis Pitsiladis  17Noriyuki Fuku  54Paul W Franks  55  56  57Kathryn N North  33Cornelia M van Duijn  3Karen A Mather  11Torben Hansen  9  58Ola Hansson  10Tim Spector  12Joanne M Murabito  59  60J Brent Richards  5  6  12  61Fernando Rivadeneira  2  3Claudia Langenberg  1John R B Perry  1Nick J Wareham  1Robert A Scott  1
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Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness

Sara M Willems et al. Nat Commun..

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.

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Conflict of interest statement

R.A.S., D.K.R., A.P. and D.M.W. are employees of GlaxoSmithKline plc. The remaining authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Association of the 16 SNV grip strength score with grip strength by age and sex strata.
Association of the grip strength-increasing genetic score showed no interaction with observed grip strength by age (pinteraction=0.30) but was stronger in men than in women (Pinteraction=1.56 × 10−5) in a subset of 111,860 unrelated UK Biobank participants from stage one analyses. Associations shown are from linear regression.
Figure 2
Figure 2. MetaXcan-predicted association of predicted gene transcript levels with grip strength across biologically relevant tissues in GTEx.
Data are shown for all genes at which altered transcription was significantly associated with grip strength in at least one biologically relevant tissue, after accounting for multiple testing. Data arez-scores of transcript level association with higher handgrip strength, clustered by tissue. Direction ofz-score indicates whether higher or lower gene expression is associated with higher grip strength. Absolutez-score>1.96 indicates nominal significance atP≤0.05, and ≥4.94 indicates significance after adjustment for multiple testing (P≤7.91 × 10−7). NAcc, nucleus accumbens.
Figure 3
Figure 3. Mendelian randomization estimates of the association of grip strength with mortality and morbidity outcomes.
(a) Mortality and parental lifespan in UKB and EPIC-Norfolk; (b) forearm bone mineral density (BMD), lumbar spine BMD and femoral neck BMD in GEFOS; (c) coronary heart disease and myocardial infarction in CARDIoGRAMplusC4D, and fracture risk in GEFOS+EPIC-Norfolk; (d) lean mass index and fat mass index in the Fenland Study+EPIC-Norfolk (n=12,851). Error bars reflect 95% CI.
See this image and copyright information in PMC

References

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