Abstract
Appendicular lean mass (ALM) is a heritable trait associated with loss of lean muscle mass and strength, or sarcopenia, but its genetic determinants are largely unknown. Here we conducted a genome-wide association study (GWAS) with 450,243 UK Biobank participants to uncover its genetic architecture. A total of 1059 conditionally independent variants from 799 loci were identified at the genome-wide significance level (p < 5 × 10−9), all of which were also significant at p < 5 × 10–5 in both sexes. These variants explained ~15.5% of the phenotypic variance, accounting for more than one quarter of the total ~50% GWAS-attributable heritability. There was no difference in genetic effect between sexes or among different age strata. Heritability was enriched in certain functional categories, such as conserved and coding regions, and in tissues related to the musculoskeletal system. Polygenic risk score prediction well distinguished participants with high and low ALM. The findings are important not only for lean mass but also for other complex diseases, such as type 2 diabetes, as ALM is shown to be a protective factor for type 2 diabetes.
Highlights
Appendicular lean mass (ALM) is a heritable trait associated with loss of lean muscle mass and strength, or sarcopenia, but its genetic determinants are largely unknown
The study sample came from the UK Biobank (UKB) cohort, which is a large prospective cohort of ~500,000 participants from across the United Kingdom, aged between 48 and 73 at recruitment
This measurement of lean mass is reliable based on its strong correlation with ALM measured by dual-energy X-ray absorptiometry (DEXA) in 4294 UKB participants (Pearson’s correlation coefficient 0.96, p < 2.2 × 10–16)
Summary
Appendicular lean mass (ALM) is a heritable trait associated with loss of lean muscle mass and strength, or sarcopenia, but its genetic determinants are largely unknown. A key reason for the limited findings, as in other human complex traits, is the modest sample size used in most GWASs performed for lean body mass[9,10,11,12,13], resulting in few single nucleotide polymorphisms (SNPs) identified with genome-wide significance. Despite the large sample used, the percentage of phenotypic variance explained by the identified SNPs was still only 0.23% and 0.16% for whole body lean mass and ALM, respectively, suggesting that most of the heritability of lean body mass was still undetected. Even with such a large GWAS meta-analysis, it is still necessary to boost the sample size further to enhance the statistical power for detecting more causal SNPs underlying lean body mass. 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
