AQP4-ab-Positive Neuromyelitis Optica Spectrum Disorder Increases the Risk of Hydrocephalus: A Bidirectional Mendelian Randomization Study.

Introduction: Some observational studies indicated that AQP4-ab-positive neuromyelitis optica spectrum disorder (NMOSD) may predispose to hydrocephalus. However, the causal relationship between NMOSD and hydrocephalus remains elusive. We used bidirectional Mendelian randomization (MR) to examine the causal effect of AQP4-ab-positive NMOSD and hydrocephalus.

Methods: The exposure GWAS data used in this study were obtained from the GWAS Catalog, which included 132 AQP4-ab-positive patients and 1244 normal controls. The outcome GWAS data for hydrocephalus (N__case = 2455, N__control = 382,198) were obtained from FinnGen R10. We used the inverse-variance weighted (IVW) method to perform the principal analyses. Then, we used the Cochrane Q-statistics test to assess the presence of heterogeneity and MR-Egger‑intercept test to evaluate the pleiotropy for sensitivity analyses. A reverse MR analysis was used to investigate the potential for reverse causation.

Results: In the IVW analysis, we found that genetically predicted AQP4-ab-positive NMOSD was significantly associated with the increasing risk of hydrocephalus (OR = 1.05; 95% CI: 1.02-1.08; p = 7.65 × 10^-5). In reverse MR analysis, we did not find genetically predicted hydrocephalus significantly associated with AQP4-ab-positive NMOSD (p > 0.05). In the sensitivity analysis, both the primary and reverse MR results exhibit no heterogeneity and horizontal pleiotropy.

Discussion: Our results indicate that genetically predicted AQP4-ab-positive NMOSD significantly increases the risk of hydrocephalus. The reduced immune activity of AQP4 may play an important role in the pathogenesis of hydrocephalus.