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 DM., McCarthy MI., Pedersen O., Khaw K-T., Kiel DP., GEFOS Any-Type of Fracture Consortium None., 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.
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.