Abstract
Muscle bulk in adult healthy humans is highly variable even after accounting for height, age and sex. Low muscle mass, due to fewer and/or smaller constituent muscle fibres, would exacerbate the impact of muscle loss occurring in aging or disease. Genetic variability substantially influences muscle mass differences, but causative genes remain largely unknown. In a genome-wide association study (GWAS) on appendicular lean mass (ALM) in a population of 95,545 middle-age (37-48 years) individuals from the UK Biobank we found 125 loci associated with ALM (P<5×10-8). We replicated associations for 64% of these loci (P<5×10-8) with ALM in a population of 193,688 elderly (65-74 years) individuals. We also conducted a GWAS on skeletal muscle mass of 1,867 mice from the LGSM advanced intercross line and found 23 quantitative trait loci. Five loci and nine positional candidates overlapped between the two species. In vitro studies of potential candidates identified CPNE1 and STC2 genes as novel modifiers of myogenesis. Collectively, these findings shed new light on the genetics of muscle mass variability in humans and identified new targets for the development of interventions preventing muscle loss. The overlapping genes between humans and the mouse model will facilitate understanding of the cellular mechanisms underlying muscle variability.
Footnotes
The revision contains expanded population of the elderly individuals used in the analyses, the mouse model data and the in vitro validation of the candidate genes. Supplementary information and the authorship are updated accordingly to reflect those additions.