Genome-wide Association Studies of over 30,000 Samples with Bone Mineral Density at Multiple Skeletal Sites and Its Clinical Relevance

Abstract The ultimate goal of a genome-wide association study (GWAS) is to translate its discoveries into clinical practice. To explore the clinical use of GWAS findings in the bone field, we conducted a GWAS of dual-energy X-ray absorptiometry (DXA)-derived bone mineral density (BMD) traits at 11 skeletal sites, within over 30,000 European individuals from the UK Biobank. A total of 91 unique and independent loci were identified for 11 DXA-derived BMD traits and fractures, including five novel loci (harboring the genes ABCA1, CHSY1, CYP24A1, SWAP70, and PAX1) for six BMD traits. These loci exhibited evidence of association in both males and females, which could serve as independent replication. We demonstrated that each polygenic risk score (PRS) was independently associated with fracture risk. Although incorporating multiple PRSs (ie, metaPRS) with clinical risk factors from the Fracture Risk Assessment Tool exhibited the highest predictive performance, the improvement was modest in fracture prediction. Additionally, we uncovered genetic correlation and shared polygenicity between head BMD and intracranial aneurysm. Finally, by integrating gene expression and GWAS datasets, we prioritized genes (e.g., ESR1 and SREBF1) encoding druggable human proteins along with their respective inhibitors/antagonists. In conclusion, this comprehensive investigation revealed a new genetic basis for BMD and its clinical relevance to fracture prediction. More importantly, it is suggested that head BMD was genetically correlated with intracranial aneurysm. The prioritization of genetically supported targets implies the potential repurposing of drugs (e.g., the n-3 PUFA supplement) for the prevention of osteoporosis.