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Author Spotlight: Methodologies and Advancements of Chronic Pain Management Research
Published on: January 5, 2024
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.
Background:
Multiple sclerosis (MS) is associated with widespread network disruption, but whether specific white-matter structural connectivity (WMSC) phenotypes contribute causally to MS susceptibility remains unclear.
Methods:
We performed bidirectional two-sample Mendelian randomization (MR) using genome-wide association study (GWAS) summary statistics for 206 tractography-derived WMSC phenotypes (UK Biobank; N = 26,333) and MS susceptibility (IMSGC; N = 115,803 of European ancestry). Primary inference used inverse-variance weighted (IVW) MR under a multiplicative random-effects model, complemented by MR-Egger, weighted median, weighted mode, and simple mode.
Results:
In forward MR, 12 WMSC phenotypes remained associated with MS susceptibility after direction-concordance filtering and robustness assessment. These signals were not randomly distributed across the structural connectome: risk-increasing effects were concentrated in salience/control-related cortico-subcortical and sensorimotor couplings, particularly connections involving the amygdala, putamen, and contralateral somatomotor network, whereas inverse associations were more prominent in default-mode/limbic and cross-network connections, including limbic-accumbens, limbic-caudate, default-mode-hippocampus, and visual-default-mode links. Sensitivity analyses did not indicate directional pleiotropy, outlier-driven distortion, or single-variant dependence among the retained traits. No reverse causal effect of MS liability on the prioritized WMSC phenotypes was supported.
Conclusions:
These bidirectional MR results support a circuit-selective model in which genetically influenced variation in specific cortico-subcortical WMSC phenotypes is associated with MS susceptibility, with risk-increasing effects concentrated in salience/control-basal ganglia-sensorimotor circuits and inverse associations enriched in default-mode/limbic and cross-network couplings. The absence of robust reverse effects is more consistent with predisposing connectivity architectures than with MS liability causally altering WMSC.
Insights
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.
