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

Sara M. Willems

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.

Muscle strength, measured by isometric hand grip strength, is an accessible and widely used proxy of muscular fitness. Lower grip strength is associated with impaired quality of life in older adults, and is an established marker of frailty, predicting physical decline and functional limitation in daily living1,2,3. The value of grip strength as a clinical predictor of fracture risk has been demonstrated in different populations4,5, and higher grip strength has been found to be prognostic of walking recovery after hip fracture surgery in later life6. Grip strength has also been shown to predict cardiovascular disease (CVD) and all-cause mortality over many years of follow-up7,8,9. Whilst it remains unclear whether these prospective associations with fracture risk, CVD and mortality are causal—or reflect early manifestation of underlying disease processes—the role of muscular strength as a predictor of functional capacity highlights the importance of understanding its aetiology.

Grip strength is highly heritable (h2=30–65%)10,11,12. Whilst candidate gene approaches have implicated multiple loci in this phenotype, including thermogenic and myogenic factors13,14, there remain few robustly replicated associations. Two genome-wide association studies in up to 27,000 individuals have been reported to date15,16, yielding one intergenic genome-wide significant association16.

Here, in a combined sample size of 195,180 individuals, including 142,035 individuals from the UK Biobank (UKB) cohort17, we identified 16 genome-wide significant loci associated with grip strength. We also performed Mendelian randomization (MR) analyses, which showed no evidence for causality in the associations of grip strength with CVD or all-cause mortality, but were suggestive of a causal effect of muscular strength on fracture risk.


Multiple novel loci are associated with grip strength

In stage one analyses, we tested the association of >17 million variants (minor allele frequency (MAF)>0.1%, imputation quality >0.4), in 142,035 white European individuals from UK Biobank (Supplementary Table 1) with maximal grip strength. Genome-wide single-nucleotide variant (SNV) heritability was estimated at 23.9% (SE 2.7%). Twenty-one loci showed genome-wide significant associations (P<5 × 10−8) in stage one (Supplementary Fig. 1), and were subsequently followed up in stage two analyses of up to 53,145 individuals from 8 additional studies (Supplementary Table 1; Supplementary Note) including the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium16. Twelve loci were independently replicated (directional consistency with stage one, P<0.05) in stage two cohorts (Supplementary Table 2A) and 16 loci contained genome-wide significant associations (P<5 × 10−8) in combined analyses. Effect sizes on grip strength ranged from 0.14 to 0.42 kg per allele under an additive model (Table 1; Supplementary Fig. 1; Supplementary Table 2A and B). Given the discordance in sample size between stage one and two analyses, and in the interests of maximizing power, we considered there to be evidence of association at any locus reaching genome-wide significance in combined analyses, and pursued all 16 in downstream analyses. Lead SNVs at the 16 grip strength-associated loci included common variants (MAF≥5%) in or near POLD3, TGFA, ERP27, HOXB3, GLIS1, PEX14, MGMT, LRPPRC, SYT1, GBF1, KANSL1, SLC8A1, IGSF9B, ACTG1, a low-frequency variant (MAF 3%) in DEC1, and a further common variant falling within the human leukocyte antigen (HLA) region (Table 1; Supplementary Fig. 2). Approximate conditional analyses identified no additional signals at genome-wide significance at these 16 loci after conditioning on their respective lead SNVs. At two loci, we saw evidence for a departure from additivity (P<3.13 × 10−3 under a dominance deviation model (see Methods)); at the GBF1 locus, we saw evidence for a dominant effect of the grip strength-raising A allele (Pdomdev=2.3 × 10−3; Supplementary Fig. 3A), and at the SYT1 locus, we saw evidence for a recessive effect of the grip strength-raising A allele (Pdomdev=3.0 × 10−3; Supplementary Fig. 3B). No individual variants showed significant effect modification by age or sex (Supplementary Table 2C and D). The association of the 16 SNV genetic score (modelled as the sum of the grip strength-increasing allele dosage at each SNV per individual) showed no interaction with age (Pinteraction=0.30), but was stronger in men than in women (men: β=0.20 kg per grip strength-increasing allele, P=2.38 × 10−48; women: β=0.13 kg per grip strength-increasing allele, P=3.61 × 10−43; Pinteraction=1.56 × 10−5; Fig. 1; Supplementary Table 2C and D). Age at recruitment was independent of strength-increasing allele dosage at each of the 16 SNVs from combined analyses. Equally, allele frequency at each SNP was not predicted by age, suggesting that there is no selection of alleles by age at these loci18. We did not replicate the previously-reported association at rs752045 with grip strength16 (β per minor allele (95% confidence interval (CI))=0.01 (−0.06, 0.08), P=0.75)


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