Genome-wide association study and polygenic risk score analysis for bipolar disorder in the Korean population

This study aimed to identify common genetic variants associated with bipolar disorder (BD) in the Korean population and to evaluate the predictive performance of polygenic risk scores (PRSs) derived from other population data. A cohort of 1538 individuals diagnosed with bipolar I or II disorder (DSM-IV) and 2271 healthy controls were recruited from seven academic institutions and their affiliated hospitals in South Korea through the Korean Psychiatric Genome-Wide Association Study (GWAS) Project. After imputation, 7655,788 single-nucleotide polymorphisms (SNPs) were analyzed for the association with BD. For the PRS analysis, we utilized the latest GWAS summary statistics from the Psychiatric Genomics Consortium for BD and schizophrenia. We identified one genome-wide significant locus, rs75776799, an intronic SNP in the solute carrier family 25 member 12 gene (P = 2.45 × 10⁻⁹; odds ratio = 2.65; 95% confidence interval = 1.92-3.64; effect allele frequency = 0.0398), which has been previously implicated in autism spectrum disorder. Summary data-based Mendelian Randomization (SMR) analysis using East Asian mQTL data identified several CpG probes mapping to DLX2-AS1 and ITGA6 showing a suggestive association with BD. The PRS analysis revealed the highest explained variances of BD in the Korean sample when using multi-ancestry BD GWAS data. This study identified a genome-wide significant locus in this cohort for BD, which suggests a potential role of mitochondrial function in its pathogenesis, expanding our understanding of the genetic architecture of BD.