The contribution of specific molecular-genetic factors to muscle mass variation and sarcopenia remains largely unknown. To identify endogenous molecules and specific genetic factors associated with appendicular lean mass (APLM) in the general population, cross-sectional data from the TwinsUK Adult Twin Registry were used. Non-targeted mass spec-based metabolomic profiling was performed on plasma of 3953 females (mostly dizygotic and monozygotic twins). APLM was measured using dual-energy X-ray absorptiometry (DXA) and genotyping was genome-wide (GWAS). Specific metabolites were used as intermediate phenotypes in the identification of single-nucleotide polymorphisms associated with APLM using GWAS. In all, 162 metabolites were found significantly correlated with APLM, and explained 17.4% of its variation. However, the top three of them (unidentified substance X12063, urate, and mannose) explained 11.1% (P ≤ 9.25 × 10(-26)) so each was subjected to GWAS. Each metabolite showed highly significant (P ≤ 9.28 × 10(-46)) associations with genetic variants in the corresponding genomic regions. Mendelian randomization using these SNPs found no evidence for a direct causal effect of these metabolites on APLM. However, using a new software platform for bivariate analysis we showed that shared genetic factors contribute significantly (P ≤ 4.31 × 10(-43)) to variance in both the metabolites and APLM--independent of the effect of the associated SNPs. There are several metabolites, having a clear pattern of genetic inheritance, which are highly significantly associated with APLM and may provide a cheap and readily accessible biomarker of muscle mass. However, the mechanism by which the genetic factor influences muscle mass remains to be discovered.