| Title: | Causal neurodevelopmental origins of scoliosis: Multi-omics Mendelian randomization reveals brain-region-specific pathways and protein mediators |
| Journal: | Journal of Orthopaedic Translation |
| Published: | 22 Dec 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41836545/ |
| DOI: | https://doi.org/10.1016/j.jot.2025.09.010 |
Publication 17280
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Abstract
Background: The causal relationship between early-life central nervous system (CNS) infections and adolescent idiopathic scoliosis (AIS) remains unresolved, with limited evidence on mediating mechanisms linking neuroanatomical changes to spinal deformity.</p>
Method: Through three longitudinal cohorts (n = 57875) and two-step Mendelian randomization (MR) integrating neuroimaging genomics (UK Biobank) and proteomics, we dissected causal pathways from childhood viral encephalitis (VE) to scoliosis. We employed inverse-variance weighted (IVW), MR-Egger regression, and sensitivity analyses (MR-PRESSO) to control for pleiotropy and reverse causation.</p>
Results: Childhood VE was associated with a 3.6-fold increased risk of scoliosis (HR = 3.604, 95 % CI: 3.121-4.163, P = 0.001), with lesions in the corpus callosum and cerebellum showing the strongest effects. MR analysis identified seven imaging-derived phenotypes (IDPs) causally linked to scoliosis, including grey matter volume in the left thalamus (OR = 1.451) and isotropic free water fraction in the cerebellar peduncle (OR = 2.408). Mediation MR revealed that brain protein ERBB4 and cerebrospinal fluid protein LBP mediated 34.9 % of the total effect (β = -0.181), highlighting their role in bridging neuroinflammation to spinal deformity.</p>
Conclusion: This study offers suggestive evidence for a causal pathway from childhood CNS infections to scoliosis, mediated by specific brain-region damage and protein biomarkers.</p>
The translational potential of this article: Clinically, the results support the implementation of scoliosis screening programs in children recovering from CNS infections.</p>
12 Authors
- Shuhao Zhang
- Sisi Lu
- Shiyu Chen
- Xiangxiang Pan
- Dongdong Xia
- Lue Liu
- Chenglong Xie
- Majid Nisar
- Aimin Wu
- Xiaolei Zhang
- Xiangyang Wang
- Chongan Huang
1 Application
| Application ID | Title |
|---|---|
| 323644 | The Impact of Childhood Illnesses on Adolescent Spinal Deformities |
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