Uncovering the genetic underpinnings for different psychiatric disorder combinations

Psychiatric disorders are highly heterogeneous, and it is clinically meaningful to distinguish psychiatric disorders by the presence or absence of a specific comorbid condition. In this study, we employed a recently developed algorithm (CombGWAS) to decipher the genetic basis of psychiatric disorder combinations. The focus was on comorbidities and combinations of disorders, such as major depressive disorder(MDD) with and without schizophrenia(SCZ), which can be considered as two subtypes of MDD. We also studied psychiatric disorders comorbid with obesity as disease subtypes. Our study identified genetic variants associated with different subtypes and the genetic architecture underlying the 16 psychiatric disorder combinations. We also performed further analysis including gene-based (MAGMA), tissue specificity, and pathway enrichment analyses. Genetic correlation and Mendelian randomization(MR) analysis were also performed across different psychiatric disorder subtypes, and with various cardiovascular diseases(CVD). We identified 653 risk loci associated with the 16 psychiatric disorder entities. While high genetic correlations(rg) were observed between many subtypes, MDD with and without obesity only showed modest genetic correlation(rg=0.166). Interestingly, most subtype pairs exhibited distinct genetic correlations with the same cardiovascular disease. Some pairs even displayed opposite genetic correlations. For instance, the genetic correlation(rg) between SCZ with obesity and type 2 diabetes(T2DM) was 0.248(p=4.42E-28), while rg between SCZ without obesity and T2DM was -0.154(p=6.79E-12). Using MR, we observed that many psychiatric comorbidities may be causally linked to increased CVD risks, but the effect size differed substantially. Comorbid psychiatric disorders typically display different causal effects with CVD compared to single psychiatric disorders without comorbidities. This study represents a significant step toward unravelling the heterogeneity underlying psychiatric disease combinations and comorbidities, shedding light on their underlying pathophysiology.