Genome-wide association study of sarcopenia index reveals sex-stratified genetic architecture
TL;DR
The genetic architecture of SI is clarified and sex-dependent mechanisms underlying sarcopenia are revealed, supporting precision risk assessment and targeted interventions and supporting precision risk assessment and targeted interventions.
Abstract
The 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. We 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. We 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− 9) and metabolic syndrome (rg = −0.12, p = 8.49 × 10− 8), and a positive correlation with chronic kidney disease. Compared with female SI, male SI exhibited two additional loci showing colocalization with four metabolic traits. These findings clarify the genetic architecture of SI and reveal sex-dependent mechanisms underlying sarcopenia, supporting precision risk assessment and targeted interventions. Sex-stratified GWAS identified 247 loci reaching genome-wide significance in only one sex among 774 independent SI-associated loci, of which 59 showed stronger associations in the corresponding sex-stratified GWAS than in the combined-sex analysis. The rs1145093–chr15q21.1–GATM region showed a prominent sex-dependent association via sex-stratified analyses. Sex-stratified functional annotation pointed to male-enriched androgen receptor and GATA4, female-enriched ESR1 and MYOD1, and common biological processes related to inflammation, stress response, and aging. Cross-phenotype colocalization identified rs1229984 at chr4q23 and rs9817452 at chr3q25.31 as loci showing male-stratified colocalization with four metabolic traits.