Exploring the Shared Genetic Architecture of Sarcopenia Using Genomic Structural Equation Modeling.

BACKGROUND: Sarcopenia is a common age-associated condition characterized by the progressive loss of skeletal muscle mass, strength, and physical functionality. While large-scale genome-wide association studies (GWAS) have previously addressed isolated traits of sarcopenia, the multifactorial genetic architecture underlying this condition remains largely undefined. METHODS: To characterize the common genetic basis of sarcopenia-related traits, genomic structural equation modeling (Genomic-SEM) was implemented. Multiple post-GWAS analytic approaches were integrated to pinpoint susceptibility loci. These analyses encompassed identifying enriched genetic pathways and relevant genomic elements, as well as cell-type-specific enrichment in skeletal muscle satellite stem cells, mesenchymal stem cells, and skeletal muscle satellite cells in limb muscle. Furthermore, based on the integrated GWAS data of sarcopenia-related traits, polygenic risk score (PRS) analysis was conducted to evaluate risk associations at the chromosomal level. RESULTS: A well-fitted Genomic-SEM successfully integrated the GWAS data, revealing the shared genetic architecture of sarcopenia-related traits. We identified 110 single nucleotide polymorphisms (SNPs) reaching genome-wide significance (P < 5 × 10-8), of which 9 represent novel discoveries. Subsequent fine-mapping procedures and gene-set analyses identified 15 causal variants alongside 77 candidate susceptibility genes. CONCLUSION: This study provides a comprehensive genetic characterization of sarcopenia via Genomic-SEM, offering new insights into the etiological pathways underlying sarcopenia.