Uncovering Potential Genetic Targets in the Mediating Role of Demyelinating Disease for Multiple Sclerosis-Induced Neuropathic Bladder: A Mendelian Randomization Analysis

Abstract Objective Despite the lack of a genetic explanation for the causal link between multiple sclerosis (MS) and neuropathic bladder (NPB), our study aims to explore this causality and underlying mechanisms using Mendelian Randomization (MR), aiming to identify novel protein targets for future therapeutic interventions.Methods Data pertaining to MS, demyelinating diseases (DD), neurogenic bladder, and plasma proteins were sourced from the IEU Open GWAS Project and encompassed a diverse population. After stringent screening, a bidirectional two-sample MR analysis was first conducted to establish the causality between MS and NPB. DD was then introduced as a mediator for further testing via the product of coefficients approach. Subsequently, plasma proteins were analyzed as exposures against the aforementioned phenotypes to screen for potential therapeutic targets.Results Our analysis substantiates that MS is associated with an increased risk of developing NPB (P-value = 0.001), with no evidence of reverse causality, reinforcing the unidirectional impact of MS on NPB. The mediation analysis revealed a clear causal pathway, supporting the hypothesis that DD serves as a crucial intermediary in the progression from MS to NPB (P-value = 0.005, mediation proportion = 70.29%). Notable proteins such as ADAM11, GRIA4, CXCL13, and PRKCG were identified, and by relaxing the FDR constraints, GSR and UBA2 were also pinpointed as potential risk factors for both MS and NPB.Conclusions Our MR analysis elucidated the causal connections among MS, DD, and NPB from a genetic perspective, identifying potential protein targets that facilitate future drug development and therapeutic strategies.