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Genetic Variants Associated With Muscle Strength Uncovered in New Study

NEW YORK (GenomeWeb) – Researchers have linked 16 loci to grip strength in a new genome-wide association study.

Grip strength is a commonly used stand-in for muscle fitness and has been linked to mortality, cardiovascular disease, and fracture risk. By drawing on the UK Biobank and other cohorts, researchers from the University of Cambridge and elsewhere conducted a large-scale GWAS to home in on loci associated with grip strength. As they reported today in Nature Communications, a number of the loci they found are located in or near genes with roles in skeletal muscle fiber structure and function.

"While we have long suspected a role for genetics in the variation in muscle strength, these findings give the first insights into some of the specific genetic variants that underpin variation in strength," senior author Robert Scott, from the MRC Epidemiology Unit at Cambridge, said in a statement.

The researchers examined the association of more than 17 million variants with grip strength — as assessed by a hydraulic hand dynamometer — in 142,035 white Europeans from the UK Biobank, and linked 21 loci with grip strength. In a follow-up analysis of 53,145 people from eight other studies, they replicated 12 loci, and, in a combined analysis, reported 16 loci had genome-wide significant associations with grip strength.

These loci included variants in or near ACTG1, TGFA, and POLD3, among others. A number of these genes have roles in biological processes associated with muscle function, the researchers said. For instance, ACTG1 encodes part of the costamere, which connects the muscle sarcomere to the cell membrane. When it's knocked out in mice, those mice exhibit muscle weakness, progressive myopathy, and other muscle-related effects. Meanwhile, TGFA encodes transforming growth factor alpha, which has a neurotrophic role in the central and peripheral nervous systems, and promotes neuronal survival after motor neuron injury.

Additionally, some of the grip-strength loci are near genes that have been implicated in monogenic disorders that are marked by neurological or psychomotor symptoms. One loci — rs10186876 — is upstream of LRPPRC, which has been connected to the neurological disorder Leigh Syndrome among French Canadians.

In a series of Mendelian randomization analyses, the researchers also examined links between grip strength and disease or mortality. While they found no evidence for a causal relationship between muscular strength and all-cause mortality or coronary heart disease, they did find a link between it and fracture risk.

Similarly, they noted a genome-wide genetic correlation between bone mineral density and grip strength, which they said supported the notion of a link between higher grip strength and fracture risk. The researchers also uncovered a genetic correlation between grip strength and lean mass index. These findings, they added, support the use of strength training to reduce fracture risk.

"This work highlights the importance of muscle strength in the prevention of fractures and the complications which can often follow a fall," added senior author Nick Wareham, director of the MRC Epidemiology Unit.