| Title: | Meta-ERS: an exposome-based risk score using non-genetic factors to guide osteoporosis prevention |
| Journal: | Journal of Translational Medicine |
| Published: | 8 Jun 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42260587/ |
| DOI: | https://doi.org/10.1186/s12967-026-08379-5 |
Publication 20742
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Abstract
BackgroundOsteoporosis is influenced by both genetic and environmental factors, yet the relative contribution of the exposome remains unclear. This study aimed to systematically identify non-genetic exposures related to osteoporosis and develop an exposome risk score (ERS) to evaluate individual osteoporosis susceptibility.MethodsWe conducted an exposome-wide analysis of 477,792 UK Biobank participants to identify key exposures associated with osteoporosis. The selected exposures were combined into a weighted Meta-ERS and validated in the Scotland/Wales cohort. The Meta-ERS was further compared with polygenic risk scores (PRS) and linked to plasma proteomics to explore underlying biological pathways.ResultsWe identified 41 independent non-genetic exposures spanning socioeconomic status, mental health, sleep, diet, smoking, physical activity, environment, and marital status, with socioeconomic status and mental health emerging as the most significant drivers. Based on the identified exposures, we constructed eight domain-specific exposure risk scores and integrated them into a weighted Meta-ERS. The Meta-ERS (R2 = 5.1%; Proportion of Chi−Square = 14.3%) demonstrated an ability to explain osteoporosis variation that was on par with polygenic risk scores (R2 = 4.8%; Proportion of Chi−Square = 12.0%). Importantly, modifying unfavorable exposures mitigated the negative effect of PRS on osteoporosis, particularly among high PRS individuals (1.5- to 1.8-fold greater absolute risk reduction than in those with low PRS). Proteomic analyses further revealed potential mechanisms through which the exposome influences osteoporosis, including hormonal regulation, inflammation, ossification, muscle development, lipid metabolism, and accelerated bone aging. Among these, growth/differentiation factor 15 was identified as a key mediator protein, with a mediation proportion of 13.13%-36.52%.ConclusionsThe Meta-ERS facilitates the quantification of individual osteoporosis risk and identifies modifiable exposures for targeted prevention. Its application can enable personalized risk stratification and guide lifestyle or environmental interventions.</p>
9 Authors
- Yi Zheng
- Yucan Li
- Yawen Gao
- Jincheng Li
- Chen Suo
- Yanfeng Jiang
- Li Jin
- Kelin Xu
- Xingdong Chen
1 Application
| Application ID | Title |
|---|---|
| 92718 | Deciphering chronic disease - association studies of genome, exposome and phenome |
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