| Title: | Genome-wide Association Studies of over 30,000 Samples with Bone Mineral Density at Multiple Skeletal Sites and Its Clinical Relevance |
| Journal: | Genomics Proteomics & Bioinformatics |
| Published: | 28 Oct 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41206123/ |
| DOI: | https://doi.org/10.1093/gpbjnl/qzaf097 |
| URL: | https://academic.oup.com/gpb/advance-article-pdf/doi/10.1093/gpbjnl/qzaf097/65229532/qzaf097.pdf |
Publication 19126
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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 5 novel loci (harboring the genes ABCA1, CHSY1, CYP24A1, SWAP70, and PAX1) for 6 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 (i.e., metaPRS) with clinical risk factors from the Fracture Risk Assessment Tool (FRAX) yielded 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 (IA). 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 reveals a new genetic basis for BMD and its clinical relevance to fracture prediction. More importantly, it suggests that head BMD is genetically correlated with IA. The prioritization of genetically supported targets implies the potential repurposing of drugs [e.g., omega-3 polyunsaturated fatty acid (PUFA) supplements] for the prevention of osteoporosis.</p>
12 Keywords
- Absorptiometry, Photon
- Aged
- Bone Density
- Clinical Relevance
- Female
- Fractures, Bone
- Genome-Wide Association Study
- Humans
- Male
- Middle Aged
- Multifactorial Inheritance
- Polymorphism, Single Nucleotide
37 Authors
- Yu Qian
- Jiangwei Xia
- Pingyu Wang
- Chao Xie
- Hong-Li Lin
- Gloria Hoi-Yee Li
- Cheng-Da Yuan
- Mo-Chang Qiu
- Yi-Hu Fang
- Chun-Fu Yu
- Xiang-Chun Cai
- Saber Khederzadeh
- Pian-Pian Zhao
- Meng-Yuan Yang
- Jia-Dong Zhong
- Xin Li
- Peng-Lin Guan
- Jia-Xuan Gu
- Si-Rui Gai
- Xiang-Jiao Yi
- Jian-Guo Tao
- Xiang Chen
- Mao-Mao Miao
- Guo-Bo Chen
- Lin Xu
- Shu-Yang Xie
- Geng Tian
- Hua Yue
- Guangfei Li
- Wenjin Xiao
- David Karasik
- Youjia Xu
- Liu Yang
- Ching-Lung Cheung
- Fei Huang
- Zhenlin Zhang
- Hou-Feng Zheng
1 Application
| Application ID | Title |
|---|---|
| 41376 | Statistical genetics methods for complex traits using large-scale genomic data |
Enabling scientific discoveries that improve human health