Characterizing the polygenic overlaps of bipolar disorder subtypes with schizophrenia and major depressive disorder

Background: Large-scale studies have shown that bipolar I disorder (BD-I) and bipolar II disorder (BD-II) have differences in genetic association with schizophrenia (SCZ) and major depressive disorder (MDD). However, the underlying shared genetic architectures between BD subtypes and both SCZ and MDD remain largely unknown. Methods: We applied univariate and bivariate causal mixture models (MiXeR) to estimate the polygenicity and polygenic overlaps on large GWASs summary statistics of BD-I (n = 25,060), BD-II (n = 6781), SCZ (n = 69,369) and MDD (n = 170,756). Then, conjunctional false discovery rate approach was used to identify specific shared genetic loci between BD subtypes and both SCZ and MDD. Results: Univariate MiXeR revealed that BD-II was substantially more polygenic (22.37 K causal variants) as compared to BD-I, SCZ and MDD (7.87-12.43 K causal variants). Bivariate MiXeR revealed substantial polygenic overlaps between BD-I and SCZ (Dice-coefficient = 0.83) and between BD-I and MDD (Dice-coefficient = 0.76), which are beyond the genetic correlation (rg = 0.71 and 0.36). Conjunctional FDR analysis identified 236 distinct shared loci between BD-I and BD-II (2 loci), BD-I and SCZ (227 loci), BD-I and MDD (19 loci), BD-II and SCZ (1 locus), and BD-II and MDD (3 loci). Most of these shared loci have concordant effect directions among BD subtypes, SCZ and MDD. Limitations: The bivariate MiXeR model was not applied for the BD-II because of insufficient power and inadequate model fit. Conclusions: These findings provide evidence for extensive polygenic effects across BD subtypes, SCZ and MDD, which further our understanding of the potential genetic basis for the comorbid symptoms across these disorders.