GWAS of ~30,000 samples with bone mineral density at multiple skeletal sites and its clinical relevance on fracture prediction, genetic correlations and prioritization of drug targets

We conducted genome-wide association studies (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 92 unique and independent loci were identified for 11 DXA-derived BMD traits and fracture, including five novel loci (harboring genes such as 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 polygenic risk scores (PRSs) were independently associated with fracture risk. Although incorporating multiple PRSs (metaPRS) with the clinical risk factors (i.e., the FRAX model) exhibited the highest predictive performance, the improvement was marginal in fracture prediction. The metaPRS were capable of stratifying individuals into different trajectories of fracture risk, but clinical risk factors played a more significant role in the stratification. 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 on fracture prediction. More importantly, it was suggested that head BMD was genetically correlated with intracranial aneurysm. The prioritization of genetically supported targets implied the potential repurposing drugs (e.g. the n-3 PUFA supplement targeting SREBF1) for the prevention of osteoporosis.