Introduction: Bipolar 2 disorder (BD2) is an independent disease with specific familial aggregation, significant functional impairment, specific treatment challenges, and several distinctive clinical features. However, unlike bipolar 1 disorder, studies investigating causal and functional genes are lacking. This study aimed to identify and prioritize causal genetic variants and genes for BD2 by analysing brain-specific gene expression markers, improve the understanding of its genetic underpinnings, and support advancements in diagnosis, treatment, and prognosis. Method: We used FUMA, a genome-wide association study (GWAS) annotation tool, to pinpoint potential causal variants and genes from the largest BD2 GWAS data. Candidate causal variants most likely affecting brain gene expression were prioritized using the following criteria: (1) variants identified as eSNPs in any brain region within any brain expression quantitative trait loci (eQTL) dataset; (2) variants annotated in the Regulome database with a score <5, indicating likely functional localization; (3) the most common 15-core chromatin state across all cell types in the Roadmap Epigenomics data being ≤7, reflecting an open chromatin state; (4) localization in genomic regions with evidence of 3D chromatin interactions, as such interactions mediate genetic effects on gene expression. Results: We identified AGRN, ORMDL3, SLC25A39, RUNDC3A, NOS2, C1orf159, RP11-5407.18, RP11-465B22.3, RP11-5407.17 as candidate causal genes. These genes are associated with important pathways such as synapse formation, mitochondrial and oxidative metabolism, intracellular transport, neurotransmission, and lipid metabolism-related pathways. Conclusion: This study provides a guide for further experimental validation of functional variants, BD2-associated genes, and novel drug targets.

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