Genome-wide Associations Reveal Human-Mouse Genetic Convergence and Modifiers of Myogenesis, CPNE1 and STC2

Am J Hum Genet. 2019 Dec 5;105(6):1222-1236. doi: 10.1016/j.ajhg.2019.10.014. Epub 2019 Nov 21.


Muscle bulk in adult healthy humans is highly variable even after height, age, and sex are accounted for. Low muscle mass, due to fewer and/or smaller constituent muscle fibers, 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 85,750 middle-aged (aged 38-49 years) individuals from the UK Biobank (UKB), we found 182 loci associated with ALM (p < 5 × 10-8). We replicated associations for 78% of these loci (p < 5 × 10-8) with ALM in a population of 181,862 elderly (aged 60-74 years) individuals from UKB. We also conducted a GWAS on hindlimb skeletal muscle mass of 1,867 mice from an advanced intercross between two inbred strains (LG/J and SM/J); this GWAS identified 23 quantitative trait loci. Thirty-eight positional candidates distributed across five loci overlapped between the two species. In vitro studies of positional candidates confirmed CPNE1 and STC2 as modifiers of myogenesis. Collectively, these findings shed light on the genetics of muscle mass variability in humans and identify targets for the development of interventions for treatment of muscle loss. The overlapping results between humans and the mouse model GWAS point to shared genetic mechanisms across species.

Keywords: UK Biobank; human and mouse GWAS; sarcopenia; skeletal muscle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aging
  • Animals
  • Body Composition / genetics*
  • Body Weight
  • Calcium-Binding Proteins / genetics*
  • Case-Control Studies
  • Female
  • Follow-Up Studies
  • Genome-Wide Association Study*
  • Glycoproteins / genetics*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Male
  • Mice
  • Middle Aged
  • Muscle Development / genetics*
  • Muscle, Skeletal / cytology*
  • Muscle, Skeletal / metabolism
  • Quantitative Trait Loci
  • Thinness / genetics*


  • CPNE1 protein, human
  • Calcium-Binding Proteins
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • STC2 protein, human
  • Stc2 protein, mouse
  • copine1 protein, mouse