Uncovering Potential Susceptibility Genes for Multiple Sclerosis-Induced Neuropathic Bladder: A Mendelian Randomization Analysis

Abstract

Despite lacking a genetic explanation for the causal link between multiple sclerosis (MS) and neuropathic bladder (NPB), our study aims to explore this causality and identify novel susceptibility genes for both phenotypes. We performed linkage disequilibrium score regression to assess SNP heritability for both phenotypes. Two-sample bidirectional Mendelian randomization (MR) analyses were conducted to evaluate causal relationships between MS and NPB. We performed pathway enrichment analysis on instrumental SNPs and applied summary-data-based MR (SMR) with protein and expression quantitative trait loci. Candidate susceptibility genes were further examined through colocalization analysis and differential expression studies. Our analyses indicate a substantial genetic contribution to both MS and NPB phenotypes. MR analysis revealed that MS progression increased NPB risk (OR = 1.126; 95% CI. 1.052-1.205; p < 0.001), with no evidence of reverse causality. Pathway analysis highlighted NIK/NF-kappaB signaling and autophagosome maturation as potentially shared mechanisms. SMR (p_FDR < 0.05) and colocalization analyses (PP.H4 > 0.75) identified NFKB1 and STAT3 as candidate susceptibility genes. Transcriptomic analyses confirmed significant differential expression of these genes (p < 0.05) between MS patients and healthy controls. Our findings established a causal relationship between MS progression and NPB risk, with NFKB1 and STAT3 emerging as promising therapeutic targets for MS-induced NPB.

Keywords: Mendelian randomization; Multiple sclerosis; Neuropathic bladder; Susceptibility gene.