| Abstract: |
Background There is a clear demand for innovative therapeutics for bipolar disorder (BD). Methods We integrated the largest BD genome-wide association study (GWAS) dataset (N Case = 41 917, N Control = 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 (N Case = 1064, N Control = 365 476) and the FinnGen study (N Case = 7006, N Control = 329 192) for robust biological validation. Results Through MR analysis, we found that in the brain, downregulation of DNM3 , MCTP1 , ABCB8 and elevation of DFNA5 and PDF were risk factors for BD. In cerebrospinal fluid, increased BD risk was associated with increased levels of FRZB , AGRP , and IL36A and decreased CTSF and LRP8. Plasma analysis revealed that decreased LMAN2L , CX3CL1 , PI3 , NCAM1 , and TIMP4 correlated with increased BD risk, but ITIH1 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 LRP8. External validation further underscored the concordance between the primary and validation cohorts, confirming MCTP1 , DNM3 , PDF , CTSF , AGRP , FRZB , LMAN2L , NCAM1 , and TIMP4 are intriguing targets for BD. Conclusions Our study identified druggable proteins for BD, including MCTP1 , DNM3 , and PDF in the brain; CTSF , AGRP , and FRZB in cerebrospinal fluid; and LMAN2L , NCAM1 , and TIMP4 in plasma, delineating promising avenues to development of novel therapies. [ABSTRACT FROM AUTHOR] |
