Integrative multi-omics identifies DOC2A as a novel pharmacological target for bipolar disorder

Background Current bipolar disorder (BD) therapies suffer from limited efficacy and adverse effects, necessitating mechanistically grounded targets. Methods We integrated BD genome-wide association study data (158,036 cases; 2,796,499 controls) with brain proteomics (ROSMAP and Banner dorsolateral prefrontal cortex, n = 376 and 152) to perform proteome-wide association studies (PWAS). Bayesian colocalization and summary-data-based Mendelian randomization (SMR) prioritized causal genes. Cell-type-specific transcriptomics validated dysregulation in iPSC-derived neurons, astrocytes, and postmortem hippocampus/prefrontal cortex. Weighted gene co-expression networks (WGCNAs), functional enrichment, and molecular docking assessed functional pathways and druggability. Results PWAS identified eight BD-associated genes (false discovery rate < 0.05), with DOC2A emerging as the top candidate. Colocalization ( H 4 > 0.8) and SMR supported a causal association of DOC2A with BD, with no pleiotropy (heterogeneity in dependent instruments P > 0.01); DOC2A expression decreased in BD across neurons ( P = 4.26 × 10 −2 ), astrocytes ( P = 2.09 × 10 −2 ), hippocampus ( P = 9.80 × 10 −3 , t = −2.738), and prefrontal cortex ( P = 1.44 × 10 −2 , t = −2.580); WGCNA positioned DOC2A as a key regulator (module membership/gene significance P < 0.05) of co-expression networks enriched for BD-associated processes including neurotransmitter secretion and postsynaptic actin cytoskeleton organization ( P < 0.05); molecular docking revealed favorable-affinity binding (ΔG < −4 kcal/mol) between DOC2A and BD-related drugs and neuroprotective compounds. Conclusions Our convergent multi-omics framework highlights DOC2A dysregulation as a key contributor to synaptic dysfunction in BD and nominates it as a promising therapeutic target. The demonstrated interaction with existing neuroactive compounds provides immediate translational avenues.