A comprehensive multi-layered analysis reveals genetic pleiotropy underlying coronary artery calcification and bone mineral density

OBJECTIVES: Subclinical atherosclerosis and osteoporosis are often present together in the same individual, but their common mechanisms remain unclear. This study aims to investigate the pleiotropic relationship underlying coronary artery calcification (CAC) and estimated calcaneal bone mineral density (eBMD), providing molecular insights into their observed phenotypic associations. METHODS: Genetic correlation between CAC and eBMD was estimated based on genome-wide summary statistics. Shared loci were examined at the levels of single-nucleotide polymorphism (SNP), multi-SNP, and gene expressions to provide insights into genetic pleiotropy. Sensitivity analyses using data of DXA-derived BMD at femoral neck and lumbar spine were performed to validate key findings. Pathway enrichment analyses were conducted on significant shared loci to explore potential biological mechanisms. RESULTS: Despite an absence of a global genetic correlation, partitioning the genome into independent regions revealed five significant signals. Through subsequent multi-layered analysis, we identified 211 non-overlapping significant shared genes, including 190 from single-SNP-level, 27 from multi-SNP-level, and 3 from gene expression level, underscoring the widespread pleiotropy across CAC and eBMD. Notably, the shared signals were predominantly concentrated on chromosome 17, with SMG6 and PAFAH1B1 highlighted as crucial pleiotropic genes, and both were further confirmed by sensitivity analyses. Pathway enrichment analyses revealed oxidative stress regulation and the ubiquitin-proteasome system as critical biological mechanisms potentially linking the two traits. CONCLUSION: Our study demonstrates that the observed association between CAC and eBMD is mainly driven by pleiotropic associations.