Repurposing diuretics for bipolar disorder: a Mendelian randomization study

Despite increasing therapeutic options to treat bipolar disorder (BD), many patients fail to reach treatment targets. The study sought to explore the potential of diuretics in preventing and treating BD through Mendelian randomization (MR). We utilized a two-sample MR design to assess the relationship between diuretics usage and the risk of BD by analyzing summary statistics from a genome-wide association study (GWAS). By employing IVW-MR and SMR, the instrument effect estimates were determined through inverse-variance weighting and summary-data-based methods. Additionally, we conducted sensitivity analyses to validate the identified MR associations, including assessments of horizontal pleiotropy, colocalization, and multiple-tissue enrichment analyses. It was observed that there is a negative relationship between diuretics use and BD risk (OR = 0.93, 95% CI = 0.88–0.98, P = 6.39e-03). The overall BD risk was only associated with ADO and PRKCA gene expression at a Bonferroni-corrected threshold. SMR analysis demonstrated that a lower expression of ADO was associated with a higher risk of BD (OR 0.72, 95% CI 0.60–0.87, P = 4.71e-04). We detected no evidence of horizontal pleiotropy for the associations, and the probability of the causal variants being shared between the ADO expression and BD risk was 92.4%. SMR analysis demonstrated that a higher expression of PRKCA was linked to a greater risk of BD (OR 1.21, 95% CI 1.07–1.38, P = 3.27e-03). However, the posterior probability for a common causal variant between PRKCA expression and BD was 6.36%. Our findings identify diuretic-related molecular targets associated with BD risk and provide potential hypotheses for further investigation of the biological mechanisms and therapeutic relevance of these targets. But these findings should therefore be considered target-discovery and hypothesis-generating evidence that requires further functional, pharmacological, and clinical validation.