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

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.

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Journal
Genomics Proteomics & Bioinformatics
Published
2025-10-01
DOI
https://doi.org/10.1093/gpbjnl/qzaf097
Citations
1
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
1.82

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article

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

Ching‐Lung Cheung, Pianpian Zhao, Peng-Lin Guan, Guangfei Li et al.
1 citations
Genomics Proteomics & Bioinformatics
Genetic Associations and Epidemiology
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article

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

Ching‐Lung Cheung, Pianpian Zhao, Peng-Lin Guan, Guangfei Li, Si-Rui Gai, Hua Yue, Chun-Fu Yu, Xiangjiao Yi, Youjia Xu, Guo‐Bo Chen, Jia-Xuan Gu, Jianguo Tao, Saber Khederzadeh, Fei Huang, Hou‐Feng Zheng, Zhenlin Zhang, Mo-Chang Qiu, Geng Tian, David Karasik, Jiadong Zhong, Lin Xu, Gloria Hoi‐Yee Li, Shuyang Xie, Xin Li, Xiang Chen, Liu Yang, Yi-Hu Fang, Yu Qian, Pingyu Wang, Chao Xie, Jiangwei Xia, Hong-Li Lin, W.P. Xiao, Cheng‐Da Yuan, Mao-Mao Miao, Xiang-Chun Cai, Mengyuan Yang
article en
1 citations

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.

Genomics Proteomics & BioinformaticsVol. 23(5)
Shangrao Normal University (CN), Department of Health (CN), Binzhou Medical University (CN), Bar-Ilan University (IL), Hong Kong Polytechnic University (HK), Shandong University of Aeronautics (CN), Capital Medical University (CN), Fudan University (CN), Westlake University (CN), Soochow University (CN), Shanghai Institute for Science of Science (CN), First Affiliated Hospital of Jiangxi Medical College (CN), Second Affiliated Hospital of Soochow University (CN), Hangzhou Hospital of Traditional Chinese Medicine (CN), Shanghai Sixth People's Hospital (CN), Xijing Hospital (CN), Shanghai Center for Brain Science and Brain-Inspired Technology (CN), Hangzhou Medical College (CN), University of Hong Kong (HK), Air Force Medical University (CN)
Gujarat Council on Science and Technology, National Natural Science Foundation of China
Openalex Percentile: Top 11%
Genetic Associations and Epidemiology
1.82
DOIOpen Access PDFOpenAlex
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