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Bidirectional Mendelian randomization study of causal associations between white-matter structural connectivity and
Zhenxing Yu1, Haijun Chen1, Zhipeng Zhang1
1Department of Neurosurgery, The 908th Hospital of the Joint Logistic Support of the People's Liberation Army, Nanchang, China.
The International Journal of Neuroscience
|April 14, 2026
Summary
Genetically influenced white-matter structural connectivity (WMSC) phenotypes may causally impact multiple sclerosis (MS) susceptibility. Specific brain circuit variations, particularly in salience and sensorimotor networks, are linked to MS risk.
Area of Science:
- Neuroscience
- Genetics
- Epidemiology
Background:
- Multiple sclerosis (MS) is characterized by widespread network disruption.
- The causal role of specific white-matter structural connectivity (WMSC) phenotypes in MS susceptibility is not well understood.
Purpose of the Study:
- To investigate the potential causal relationship between WMSC phenotypes and MS susceptibility using a bidirectional Mendelian randomization (MR) approach.
- To identify specific WMSC phenotypes that may confer risk or protection against MS.
Main Methods:
- Bidirectional two-sample Mendelian randomization (MR) was employed.
- Genome-wide association study (GWAS) summary statistics for 206 WMSC phenotypes and MS susceptibility were utilized.
- Multiple MR methods (IVW, MR-Egger, weighted median, etc.) were used for robust inference.
Main Results:
- Forward MR identified 12 WMSC phenotypes associated with MS susceptibility.
- Risk-increasing effects were concentrated in salience/control, cortico-subcortical, and sensorimotor circuits (e.g., involving amygdala, putamen).
- Inverse associations were observed in default-mode/limbic and cross-network connections (e.g., default-mode-hippocampus).
Conclusions:
- Genetically influenced WMSC phenotypes are associated with MS susceptibility, supporting a circuit-selective model.
- Specific connectivity patterns in basal ganglia-sensorimotor circuits may increase MS risk.
- Default-mode/limbic network variations might be inversely associated with MS susceptibility, suggesting predisposing connectivity architectures.
