Identifying Genetic Determinants of Sarcopenia-Related Traits: a Mendelian Randomization Study of Druggable Genes

Background: Sarcopenia, characterized by progressive muscle mass and function loss, particularly affects the elderly, and leads to severe consequences such as falls and mortality. Despite its prevalence, targeted pharmacotherapies for sarcopenia are lacking. Utilizing large-sample genome-wide association studies (GWAS) data is crucial for cost-effective drug discovery. Methods: Herein, we conducted four studies to understand the putative causal effects of genetic components on muscle mass and function. Study 1 employed a two-sample Mendelian randomization (MR) on 15,944 potential druggable genes, investigating their potential causality with muscle quantity and quality in a European population (N up to 461,089). Study 2 validated MR results through sensitivity analyses and colocalization analyses. Study 3 extended validation across other European cohorts, and study 4 conducted quantitative in vivo verification. Results: MR analysis revealed significant causality between four genes (BLOC-1 related complex subunit 7, BORCS7; peptidase m20 domain containing 1, PM20D1; nuclear casein kinase and cyclin dependent kinase substrate 1, NUCKS1 and ubiquinol-cytochrome c reductase complex assembly factor 1, UQCC1) and muscle mass and function (p-values range 5.98 x 10-6 to 9.26 x 10-55). To be specific, BORCS7 and UQCC1 negatively regulated muscle quantity and quality, whereas enhancing PM20D1 and NUCKS1 expression showed promise in promoting muscle mass and function. Causal relationships remained robust across sensitivity analyses, with UQCC1 exhibiting notable colocalization effects (PP & sdot;H4 93.4 % to 95.8 %). Further validation and in vivo replication verified the potential causality between these genes and muscle mass as well as function. Conclusions: Our druggable genome-wide MR analysis identifies BORCS7, PM20D1, NUCKS1, and UQCC1 as causally associated with muscle mass and function. These findings offer insights into the genetic basis of sarcopenia, paving the way for these genes to become promising drug targets in mitigating this debilitating condition.