| Title: | Shared Genetic Architecture and Causal Relationship Between Serum 25-Hydroxyvitamin D and Bone Mineral Density |
| Journal: | The Journal of Clinical Endocrinology & Metabolism |
| Published: | 21 Oct 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39431290/ |
| DOI: | https://doi.org/10.1210/clinem/dgae738 |
Publication 13404
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Abstract
CONTEXT: Despite the well-established regulatory role of vitamin D in maintaining bone health, little is known about the shared genetics and causality of the association between serum 25-hydroxyvitamin D (25OHD) and bone mineral density (BMD).</p>
OBJECTIVE: We aimed to investigate the shared genetic architecture and causal relationship between serum 25OHD and BMD, providing insights into their underlying biological mechanisms.</p>
METHODS: Leveraging individual-level data from the UK Biobank (UKB) cohort and summary-level data from the genome-wide association studies (GWASs) conducted on European individuals for serum 25OHD (N = 417 580) and estimated heel BMD (eBMD, N = 426 824), we systematically elucidated the shared genetic architecture underlying serum 25OHD and eBMD through a comprehensive genome-wide cross-trait design.</p>
RESULTS: Despite a lack of global genetic correlation (rg=-0.001; P = .95), a statistically significant local signal was discovered at 5p11-5q11.9. Two-sample mendelian randomization (MR) indicated no causal association in the overall population (β=.003, 95% CI, -0.04 to 0.03; P = .93), while positive causal effects were observed in males (β=.005, 95% CI, 0.00 to 0.01; P = .03) and older individuals (β=.009, 95% CI, 0.00∼0.02; P = .01) according to one-sample MR. A total of 49 pleiotropic single-nucleotide variations (SNVs), with 4 novel SNVs (rs1077151, rs79873740, rs12150353, and rs4760401), were identified, and a total of 95 gene-tissue pairs exhibited overlap, predominantly enriched in the nervous, digestive, exocrine/endocrine, and cardiovascular systems. Protein-protein interaction analysis identified RPS9 and RPL7A as hub genes.</p>
CONCLUSION: This study illuminates the potential health benefits of enhancing serum 25OHD levels to mitigate the risk of osteoporosis among men and individuals older than 65 years. It also unveils a shared genetic basis between serum 25OHD and eBMD, offering valuable insights into the intricate biological pathways.</p>
12 Keywords
- Aged
- Bone Density
- Cohort Studies
- Female
- Genome-Wide Association Study
- Humans
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Polymorphism, Single Nucleotide
- United Kingdom
- Vitamin D
19 Authors
- Linna Sha
- Li Zhang
- Xunying Zhao
- Rong Xiang
- Xueyao Wu
- Jiangbo Zhu
- Jiaojiao Hou
- Qin Deng
- Chenjiarui Qin
- Changfeng Xiao
- Yang Qu
- Tao Han
- Jinyu Zhou
- Sirui Zheng
- Ting Yu
- Xin Song
- Bin Yang
- Mengyu Fan
- Xia Jiang
1 Application
| Application ID | Title |
|---|---|
| 99713 | Using genetic and phenotypic data to understand putative causal pathways leading to major human noncommunicable diseases. |
Enabling scientific discoveries that improve human health