Isolating the genetic component of mania in bipolar disorder

ObjectiveBipolar disorder typically features episodes of mania and depression, frequently accompanied by psychosis. While progress has been made in understanding the genetics of depression and psychosis, mania remains underexplored. MethodsWe employed Genomic Structural Equation Modeling to subtract the genetic effects of schizophrenia and major depressive disorder (MDD) from bipolar disorder to identify a genetic trait specific to mania. ResultsThe SEM model revealed significant loadings for "mania" (0.67, p<0.001), "psychosis" (0.58, p<0.001), and "depression" (0.29, p<0.001) factors, with mania, MDD and schizophrenia explaining 45%, 8% and 34% of the variance in bipolar disorder, respectively. Seven significant genomic regions associated with mania were identified. Key regions include rs9834970 (3q12.1, previously associated with lithium response), rs6992333 (8q13.1, brain structure), and rs12206087 (6q14.3, intelligence and cortical surface). Additionally, mania exhibited distinct genetic correlations compared to bipolar disorder across psychiatric, substance abuse, somatic, social, and neurological traits, including significantly higher correlations with intelligence (rg=0.08 vs -0.07) and educational attainment (rg=0.17 vs 0.12), and an unexpected reduced correlation with risky sexual behavior (rg=0.14 vs 0.27). ConclusionsThese findings enhance understanding of bipolar disorders genetic architecture, potentially offering a more bipolar disorder-specific GWAS.