We all experience decreasing muscle mass as we age. Appendicular lean mass (ALM) is a heritable trait associated with loss of lean muscle mass and strength and low physical performance. Decreased ALM is a major characteristic of sarcopenia, which is a more severe loss of muscle mass and strength in elderly, which can cause loss of critical functions and physical disability.
It has been reported that lean body mass has a significant genetic component, evidenced by a high heritability of 50–80% observed in twin studies. However, in previously conducted large studies, there is still not a lot knowledge between whole body lean mass and appendicular lean mass (ALM), making most of the heritability of lean body mass still undetected. Unlike ALM, which is mainly affected by skeletal muscle, whole-body lean mass is determined by skeletal muscle, smooth muscle, and cardiac muscle. Therefore, ALM has a higher predictive power for sarcopenia-related health outcomes because sarcopenia is mainly due to a low skeletal muscle amount. ALM is also slightly more heritable than whole-body lean mass and as such a more suitable trait for sarcopenia-related genetic analyses.
To understand the relationship between genetic components and ALM, researchers conducted a GWAS with 450,243 UK Biobank participants (aged between 48 and 73 at recruitment). The present study showed that 1,059 independent variants from 799 distinct loci were associated with ALM adjusted by AFM and other covariates. Of the 1,059 identified variants, 51 were missense coding variants that alter the resulting protein's function. These included common missense variants such as rs1260326 (GCKR), rs117068593 (RIN3), rs12541381 (ZFAT), rs10283100 (ENPP2), rs11545169 (PSMD2), rs2229840 (NCOR2), rs34949187 (ACAN), rs34914463 (ZBTB4), rs3764002 (WSCD2) and rs5742915 (PML). Rs1260326 (GCKR) results in an amino acid change from leucine to proline and it was previously reported to be associated with multiple metabolic traits. Rs117068593 (RIN3) results in a change of bone building proteins and is associated with both bone mass and lean mass.
This study is the largest GWAS of lean mass to date. Those over 1,000 variants accounted for ~15% of ALM variation, and that is the largest explainable fraction of variation in lean mass reported so far in a GWAS. As in other studies, certain limitations existed in this study. First, lean mass was measured by the BIA approach, which is not as reliable as the gold standards for quantifying lean mass, such as magnetic resonance imaging and computed tomography, because the latter methods are direct measures. In addition, physical activity is known to influence lean mass, the confounding effect of which was not controlled for in the present study. Read more about the study here: https://pubmed.ncbi.nlm.nih.gov/33097823/
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