Omics studies of cardiometabolic and skeletal traits

Osteoporosis and atherosclerosis are two common age-related conditions that share several clinical risk factors, yet their molecular underpinnings remain incompletely understood. This thesis applied multi-omics approaches, spanning genomics, proteomics, and metabolomics, to investigate the biological determinants of bone mineral density (BMD), trabecular bone score (TBS), and coronary artery calcification (CAC), with the aim of identifying novel biomarkers, causal pathways, and potential therapeutic targets, as well as their interrelationship.
Through large-scale genome-wide association study (GWAS) and meta-analyses, we identified genetic loci associated with femoral neck BMD, lumbar spine BMD, TBS, and CAC, and demonstrated that FN-BMD and TBS each exert independent causal effects on fracture risk. At the proteomic level, we identified ANGPTL3 as a key causal protein, reducing BMD and increasing fracture risk through adipocyte-driven osteoclastogenesis. Metabolomic analyses further identified three fatty acid ratio biomarkers associated with lower CAC burden, with several showing causal associations with coronary artery disease.
Finally, by integrating observational and genetic evidence from two independent cohorts, we found no bidirectional causal relationship between BMD and CAC, suggesting that their clinical co-occurrence is driven by shared confounders rather than shared biology. Together, these findings advance our understanding of the distinct yet overlapping molecular landscapes of skeletal and cardiometabolic disease, and highlight promising avenues for future clinical and therapeutic research.