MULTI-ANCESTRY FINE-MAPPING REVEALS BIPOLAR DISORDER RISK GENES AND HIGHLIGHTS DRUG REPURPOSING OPPORTUNITIES

Genome wide association studies (GWAS) have identified hundreds of loci contributing to bipolar disorder (BD) risk, yet identifying the causal variants and their functional roles remains a challenge owing to linkage disequilibrium (LD) between risk variants, and incomplete understanding of the non-coding regulatory mechanisms in the brain. The latest multi-ancestry GWAS meta-analysis—which integrated data from European, East Asian, African American, and Latino cohorts (comprising 158,036 cases and 2,796,499 controls)— identified 298 genome-wide significant loci for BD.

To narrow down these associated regions, we applied SuSiEx, a statistical fine-mapping method that leverages the varied LD architecture across populations, allowing us to prioritize 113 likely causal single-nucleotide polymorphisms (SNPs) within these 298 loci. These SNPs were then mapped to their corresponding genes, and we explored their functional roles for BD by integrating several lines of evidence. First, we employed Summary data-based Mendelian Randomization (SMR) to interpret these SNPs within the context of brain bulk tissue quantitative trait loci (QTLs)—covering expression, splicing, and methylation QTLs. Next, we refined the cell-type specificity of these effects using SMR analysis on a newly published resource of brain single nuclei eQTLs.

Our integrative analysis highlighted several candidate genes, including TRANK1, CACNA1B, BCL11B, RGPD8, SP4 and POU6F2, with prioritized SNPs showing regulatory effects that are specific to inhibitory and excitatory neurons as well as oligodendrocytes and astrocytes. These observations hint at potential targets for future functional studies aiming to improve our understanding of the biological mechanisms underlying BD. Future directions include drug repurposing analyses using resources such as Drugbank and the Drug Gene Interaction Database (DGIdb), to assess whether existing drugs might modulate these candidate genes to offer innovative treatments for BD.