Observational studies have proposed a link between isolated rapid eye movement sleep behavior disorder (iRBD) and several neurodegenerative diseases. We employed genome-wide linkage disequilibrium score regression (LDSC), standard two-sample Mendelian randomization (MR), and colocalization analysis to assess the causal links between iRBD and these neurodegenerative conditions. iRBD demonstrated a positive causal association with Alzheimer disease (odds ratio [OR] = 1.02, 95% confidence interval [CI]: 1.00–1.03, P = 1.10E−02), Parkinson disease (OR = 1.10, 95% CI: 1.03–1.16, P = 2.96E−03), and multiple sclerosis (OR = 1.09, 95% CI: 1.02–1.17, P = 1.61E−02). A strong positive genetic correlation with dementia with Lewy bodies was observed (rg = 1.6313, P = .0002), along with a causal association (OR = 1.45, 95% CI: 1.03–2.06, P = 3.53E−02), further supported by colocalization analysis. No significant causal relationship was identified between iRBD and amyotrophic lateral sclerosis (all P > .05). Additionally, reverse Mendelian randomization analyses did not reveal any causal relationships between the neurodegenerative diseases studied and iRBD. Our findings provide robust genetic evidence supporting a causal relationship between iRBD and the risk of multiple neurodegenerative diseases, highlighting the potential for shared pathophysiological mechanisms.
Hong Ye, Jia-Li Wang, Qiu-Han Xu et al.· Medicine· 0 citations
BACKGROUND
Trigeminal Neuralgia (TN) is a disabling facial pain disorder with suboptimal pharmacological and surgical options. We hypothesized that genetic regulation of gene expression in specific brain cell types contributes to TN susceptibility and could nominate tractable therapeutic targets.
METHODS
Single-cell cis-eQTLs from 183 neuropathology-free donors were used to instrument cell-type-specific expression. Variants surpassing genome-wide significance (P < 5×10-8) were LD-pruned (1000 Genomes Phase 3 European; r2 < 0.001; 10-Mb window) and harmonized; instruments with F < 10 were excluded. The final set comprised 1,746 Single Nucleotide Polymorphisms (SNPs) mapping to 1,745 eGenes. Two-Sample Mendelian Randomization (TwoSampleMR, R) tested eight brain cell types against TN risk in FinnGen (Release 12; 2,226 cases; 435,371 controls). Wald ratios were used for single-SNP instruments and inverse-variance weighting for multiple instruments. False Discovery Rate (FDR) control was applied within cell type. Colocalization (coloc, R) assessed shared causal variants.
RESULTS
After pruning, 1,745 eGenes were analyzed across eight cell types. A single signal met within multiple-testing control: higher astrocytic Tripartite motif-containing 66 (TRIM66) expression associated with increased TN risk (Wald ratio; β = 0.3038, standard error (SE) = 0.0884, P = 5.87×10-4; odds ratio (OR) = 1.36, 95% confidence interval (CI) 1.14-1.61; FDR = 0.0869). Colocalization supported a shared causal variant between astrocytic TRIM66 expression and TN (PP.H4 = 0.81).
DISCUSSION
Astrocyte-specific regulation of TRIM66 may contribute to TN pathogenesis through neuroinflammatory pathways, offering a cell-type-resolved mechanistic perspective that complements existing models of TN biology.
CONCLUSION
Genetic evidence suggests a potential role of astrocyte-mediated regulation of TRIM66 in TN susceptibility. Convergent MR and colocalization suggest TRIM66 as a potential cell-type-resolved candidate warranting further functional validation and therapeutic exploration.
Hong Ye, Chaoya Jiang, Zhenyan Xu et al.· Current Medicinal Chemistry· 0 citations