Shared genetic basis of sarcopenia and osteoporosis: insights from GWAS and multi-omics analyses.

Abstract

Introduction: Sarcopenia and osteoporosis are common age-related disorders, and their coexistence increases fracture risk and premature mortality. The shared genetic architecture of these conditions remains unclear.

Materials and methods: Genome-wide association study (GWAS) summary statistics from four sarcopenia-related traits were used to construct a latent factor model for sarcopenia. Osteoporosis GWAS data came from the UK Biobank and FinnGen. Linkage disequilibrium score regression and MiXeR were used to assess genetic correlation and polygenic overlap between sarcopenia and osteoporosis. Shared variants were identified via conjunctional false discovery rate (conjFDR). Key genes were analyzed with functional annotation, predicted expression, Mendelian randomization, and colocalization, and integrated with single-cell and spatial transcriptomics to reveal cell-type-specific expression and spatial patterns.

Results: Sarcopenia and osteoporosis showed a significant positive genetic correlation (rg = 0.1104, P = 1.76E-09). MiXeR estimated ~753 shared genetic variants (Dice = 0.315). conjFDR analysis identified 34 shared lead single-nucleotide polymorphisms. MetaXcan prioritized 4 and 6 comorbidity genes in subcutaneous adipose tissue and skeletal muscle, respectively (FDR < 0.05). CCND2 and CYTH1 had significant causal effects on both conditions, with colocalization indicating concordant causal variants (posterior probability of hypothesis 4 > 0.9). Genetic signals were enriched in bone- and muscle-related tissues, and CCND2 (cartilage primordium) and GRB10 (muscle) showed high tissue-specific expression for both traits.

Conclusion: Sarcopenia and osteoporosis are genetically correlated, sharing multiple polygenic signals and key comorbidity genes. Genetic effects mainly act through bone- and muscle-related tissues, supporting a shared genetic basis and potential mechanisms of bone-muscle comorbidity.