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

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 are z-scores of transcript level association with higher handgrip strength, clustered by tissue. Direction of z-score indicates whether higher or lower gene expression is associated with higher grip strength. Absolute z-score>1.96 indicates nominal significance at P≤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.

References

    1. Bohannon R. W. Hand-grip dynamometry predicts future outcomes in aging adults. J. Geriatr. Phys. Ther. 31, 3–10 (2008). - PubMed
    1. Taekema D. G., Gussekloo J., Maier A. B., Westendorp R. G. J. & de Craen A. J. M. Handgrip strength as a predictor of functional, psychological and social health. A prospective population-based study among the oldest old. Age Ageing 39, 331–337 (2010). - PubMed
    1. Rantanen T. et al.. Muscle strength as a predictor of onset of ADL dependence in people aged 75 years. Aging Clin. Exp. Res. 14, 10–15 (2002). - PubMed
    1. Cheung C.-L. et al.. Low handgrip strength is a predictor of osteoporotic fractures: cross-sectional and prospective evidence from the Hong Kong Osteoporosis Study. Age 34, 1239–1248 (2012). - PMC - PubMed
    1. Kärkkäinen M. et al.. Association between functional capacity tests and fractures: an eight-year prospective population-based cohort study. Osteoporos. Int. 19, 1203–1210 (2008). - PubMed

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