Abstract
Muscle bulk in humans is highly variable even after accounting for differences in height, age and sex, hence the impact of aging-related muscle loss known as sarcopenia varies in a similar fashion. Although heritability estimates are 40-80%, only a small number of muscle mass affecting genes have been identified. In 95,545 genotyped individuals of predominantly British ancestry, aged 37-48 years, body composition was assessed using bioelectrical impedance. We aimed to identify the genetic architecture underlying variability in appendicular lean mass (ALM), a proxy for muscle mass. A genome wide-association study (GWAS) in the Discovery cohort containing 60% of individuals identified 209 single nucleotide polymorphisms (SNP) with significant (P < 5 x 10-8) effects on ALM. We confirmed 62% of the SNPs (P < 2 x 10-5) in the remaining sub-set, the Replication cohort. A subsequent GWAS in the Combined cohort revealed 132 significant quantitative trait loci (QTLs) that collectively explained 6.75% of ALM phenotypic variance. Sixteen novel genes with missense and frameshift polymorphisms and expressed in skeletal muscle emerged (THBS3, CEP120, STC2, WSCD2, CCDC92, AKAP13, CPNE1, PPM1J, ITSN2, C2orf16, FGFR4, MLXIPL, PTCH1, BDNF, NCOR2, WDR90). Furthermore, non-coding SNPs located in 74 regulatory elements suggest gene expression being an important contributor to variation in muscle mass. In conclusion, we identified genetic architecture explaining a significant fraction of the phenotypic variation in middle age human ALM. The highlighted genes and regulatory elements will help understand the mechanisms underlying differences in skeletal muscle mass that can affect the risk and impact of sarcopenia.
- Posted July 16, 2018.
