GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium

Abstract

SummaryDecline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta‐analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P‐value< 5 × 10−8) and 39 suggestive (P‐value< 5 × 10−5) associations were observed from meta‐analysis of the discovery cohorts. After meta‐analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P‐value = 5.20 × 10−10). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer‐binding protein‐β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

Fitness, Physical Activity, and Cardiovascular Disease: Longitudinal and Genetic Analyses in the UK Biobank Study

“…To our knowledge, this is the largest study to date to combine large-scale physical activity and fitness data with genetic information. This resulted in the discovery of a much large number of genetic variants associated with grip strength compared to a recent study 34 .…”

Biological Insights Into Muscular Strength: Genetic Findings in the UK Biobank

“…The main strengths of this study include a very large sample size, which enabled us to detect a much larger number of genetic variants compared to previous studies 6,7 . We also used relative grip strength as our phenotype, which is less confounded by body size and more suitable to reflect general muscular fitness than maximal grip strength.…”

“…So far, two genome-wide association studies (GWAS) of maximal grip strength have been conducted 6,7 . The largest study, also conducted in the UK Biobank, included 195,180 individuals and identified 16 loci associated with grip strength.…”

Ageing, neurodegeneration and brain rejuvenation

“…(The epidemiology of longevity is reviewed comprehensively elsewhere 23 .) Further insights into the links between ageing and neurodegeneration are being generated from genetic studies that explore not only longevity and exceptional lifespan but also the genetics of disease-free ageing 24,25 and the integration of genetics with other omics approaches 26 .…”