ArticleBiology of sex differences2026
Genome-wide association study of sarcopenia index reveals sex-stratified genetic architecture.
Article in Biology of sex differences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundThe sarcopenia index (SI), defined as the ratio of serum creatinine to cystatin C, is a proposed biomarker of muscle mass and sarcopenia, yet its genomic basis and genetic architecture remain largely unexplored.
methodsWe performed combined-sex and sex-stratified genome-wide association studies of SI in the UK Biobank. We examined the overlap between SI-associated loci and loci previously reported for sarcopenia-related traits. We assessed sexually dimorphic effects and gene-sex interactions, performed fine-mapping, and conducted credible gene prioritization, motif and transcription factor binding enrichment, gene-set enrichment, linkage disequilibrium score regression, and cross-phenotype colocalization.
resultsWe identified 774 unique independent SI-associated loci across all analyses, with 747 detected in the combined-sex GWAS, 283 in the male-stratified GWAS, and 311 in the female-stratified GWAS; 367 of these loci had not been previously reported for conventional sarcopenia-related traits. Sex-stratified analyses highlighted the rs1145093-chr15q21.1-GATM region, where CARMA identified sex-differentiated causal variants. We prioritized 17 male-biased and 11 female-biased credible genes. Enrichment analyses implicated androgen receptor and GATA4 in males, and ESR1 and MYOD1 in females. Enrichment revealed shared pathways involving inflammation, cellular stress, and aging-related processes. LDSC showed inverse genetic correlations between SI and heart failure (rg = -0.19, p = 2.30 × 10
conclusionsThese findings clarify the genetic architecture of SI and reveal sex-dependent mechanisms underlying sarcopenia, supporting precision risk assessment and targeted interventions.
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