Uncovering novel drug targets for bipolar disorder: a Mendelian randomization analysis of brain, cerebrospinal fluid, and plasma proteomes

There is a clear demand for innovative therapeutics for bipolar disorder (BD). We integrated the largest BD genome-wide association study (GWAS) dataset ( = 41 917, = 371 549) with protein quantitative trait loci from brain, cerebrospinal fluid, and plasma. Using a range of integrative analyses, including Mendelian randomization (MR), Steiger filter analysis, Bayesian colocalization, and phenome-wide MR analysis, we prioritized novel drug targets for BD. Additionally, we incorporated data from the UK Biobank ( = 1064, = 365 476) and the FinnGen study ( = 7006, = 329 192) for robust biological validation. Through MR analysis, we found that in the brain, downregulation of , , and elevation of and were risk factors for BD. In cerebrospinal fluid, increased BD risk was associated with increased levels of , , and and decreased and . Plasma analysis revealed that decreased , , , , and correlated with increased BD risk, but did not. All these proteins passed Steiger filtering, and Bayesian colocalization confirmed that 12 proteins were colocalized with BD. Phenome-wide MR analysis revealed no significant side effects for potential drug targets, except for . External validation further underscored the concordance between the primary and validation cohorts, confirming , , , , , , , , and are intriguing targets for BD. Our study identified druggable proteins for BD, including , , and in the brain; , , and in cerebrospinal fluid; and , , and in plasma, delineating promising avenues to development of novel therapies.