Relationship between plasma proteome and hydrocephalus: a two-sample Mendelian randomization analysis

Background: Hydrocephalus is a serious condition that affects individuals across all age groups, arising from various etiologies. The substantial efficacy of plasma proteome in numerous diseases has been substantiated by multiple studies. We conducted a two-sample Mendelian randomization analysis to investigate the potential association between plasma proteome and hydrocephalus. Methods: By conducting a two-sample Mendelian randomization analysis, we identified 98 plasma proteins that either increased or decreased the risk of communicating hydrocephalus out of a total of 4,907 proteins. The inverse-variance weighted method for causal effect estimation, as well as the weighted median, maximum likelihood, and MR Egger regression methods, were further employed for sensitivity analyses after selecting the top 20 proteins. Additionally, gene enrichment analysis was performed to uncover relevant functional pathways. Results: Elevated levels of ADGRF1 (OR=2.728, 95% CI [1.266-5.879], P=0.010), APP (OR=2.923, 95% CI [1.328-6.431], P=0.008), DUSP13 (OR=3.201, 95% CI [1.062-9.647], P=0.039), EPHA3 (OR=4.341, 95% CI [1.031-18.288], P=0.045), HSPA1B (OR=4.578, 95% CI [1.431-14.643], P=0.010), HYAL1 (OR=3.075, 95% CI [1.375-6.881], P=0.006), KIRREL3 (OR=6.067, 95% CI [1.278-28.806], P=0.023), RAD23B (OR=6.825, 95% CI [1.245-37.415], P=0.027), SERPINE1 (OR=3.768, 95% CI [1.452-9.777], P=0.006), SNPH (OR=4.019, 95% CI [1.059-15.252], P=0.041), SRP14 (OR=6.292, 95% CI [1.193-33.189], P=0.030), and TMEFF1 (OR=2.830, 95% CI [1.097-7.300], P=0.031) were associated with an increased risk of hydrocephalus. Additionally, these relevant proteins primarily participate in biological processes associated with axon development, axonogenesis, axon guidance, and neuron projection guidance. Conclusion: Higher genetically predicted levels of protein ADGRF1, APP, DUSP13, EPHA3, HSPA1B, HYAL1, KIRREL3, RAD23B, SERPINE1, SNPH, SRP14 and TMEFF1 are associated with an increased risk of hydrocephalus. The findings provide valuable insights into potential therapeutic targets, protective mechanisms, and underlying biological processes, ultimately leading to the development of more effective and personalized treatment strategies for individuals with hydrocephalus.