Dissecting Immune Mechanisms Underlying Sarcopenia Using Multi-omics Approaches.

Sarcopenia is an age-related muscle disease, and its gene regulation in immune cells is not well understood. Using immune cell-specific single-cell expression quantitative trait loci (sc-eQTLs), genome-wide association studies (GWAS), and multi-omics data, we systematically explored their potential causal roles in sarcopenia. We integrated sc-eQTL and cis-eQTL data from whole blood and skeletal muscle, seven sarcopenia-related phenotypes GWAS summary statistics, and used a Muscle Function-Mass Genetic Structural Equation Model (MF-M GSEM), Mendelian randomization (MR), and Bayesian colocalization analyses to assess causal gene effects across 14 immune cell types, whole blood, and skeletal muscle. A two-step MR was then applied to explore mediation through common diseases and carnitine-related metabolites. Fourteen genes, including HLA-DRB1, HLA-C, and SLC22A5, showed significant causal effects on at least three sarcopenia phenotypes in one or more immune cell types (Bonferroni-adjusted P < 0.05; posterior probability for hypothesis 4 > 0.8). Heart failure, rheumatoid arthritis, and chronic kidney disease mediated the causal effects of sc-eQTLs for FNBP4, HLA-DRB1, HLA-C, and HLA-DQA1 on MF-M GSEM (P < 0.05). Isovalerylcarnitine (C5) mediated the causal effect of the cis-eQTL of SLC22A5 in skeletal muscle on MF-M GSEM, with a mediation proportion of 67.6% (FDR-adjusted P < 0.05). Our findings highlight that immune cell-specific expression of HLA-DRB1, HLA-C, SLC22A5, and FNBP4 contributes to the pathogenesis of sarcopenia, suggesting these genes as potential therapeutic targets and mechanistic entry points for future research.