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

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 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-age (38-49 years) individuals from the UK Biobank (UKB) we found 182 loci associated with ALM (P<5x10-8). We replicated associations for 78% of these loci (P<5x10-8) with ALM in a population of 181,862 elderly (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) which identified 23 quantitative trait loci. 38 positional candidates distributed across 5 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.

Genome-wide association study of self-reported walking pace suggests beneficial effects of brisk walking on health and survival

“…Of the 152 genes implicated by both the gene mapping and gene-based analyses, 78 remained significantly associated with self-reported walking pace following BMI adjustment. These genes included GDF5 , ACBD4 , H1FX , PTPN9 , FAM83C and UQCC1 which have previously been associated with height 17 – 20 ; MMP24 , NCOA6 , PIGU , GSS and PLCD3 , associated with lean body mass 21 , 22 ; MAPT , TRPC4AP , DCAKD , GGT7 and PROCR , associated with heel bone mineral density 23 , and several genes linked to educational attainment 24 and cognitive function 25 ( SDCCAG8 , BTN3A2 , TCF4 , HIST1H4H , ABT1 , TXNL1 , NYAP2 and ZNF322 ).…”

Genetic Associations with Aging Muscle: A Systematic Review

“…Moreover, a recent GWAS by Hernandez-Cordero et al [80] evaluated genetic contribution to ALM in the UK Biobank dataset, comparing middle-aged (38-49 years) and elderly (60-74 years) individuals. A total of 182 genome-wide significant regions, many with multiple variants within them, were associated with ALM in middle-aged individuals.…”

“…Historically, many candidate gene studies have been statistically underpowered, the replication of findings has been problematic and there has been a suspected bias against publication of negative results, which may lead to conflicting findings [130]. Many of these issues have been overcome by GWAS in large, well characterised cohorts [80,[131][132][133]. Therefore, future GWAS may help to further illuminate the genetic basis of aging muscle phenotypes.…”

The genetic architecture of appendicular lean mass characterized by association analysis in the UK Biobank study

“…In a more recent study, a GWAS of ALM was conducted in a population of 85,750 middle-aged (aged 38–49 years) individuals from the UK Biobank (UKB) 15 . A total of 182 loci were identified, 78% of which were replicated in a population of 181,862 elderly (aged 60–74 years) individuals from the same UKB cohort.…”