Exploring shared genetic bases and causal relationships of schizophrenia and bipolar disorder with 28 cardiovascular and metabolic traits

Abstract: Cardiovascular diseases (CVD) represent a major health issue in patients with schizophrneia (SCZ) and bipolar disorder (BD), but the exact nature of cardiometabolic (CM) abnormalities involved and the underlying mechanisms remain unclear. Using polygenic risk scores (PRS) and LD score regression, we investigated the shared genetic bases of SCZ and BD with a panel of 28 cardiometabolic traits. We performed Mendelian randomization (MR) to elucidate casual relationships between the two groups of disorders. The analysis was based on large-scale meta-analyses of genome-wide association studies (GWAS). We also identified the potential shared genetic variants by a statistical approach based on local true discovery rates, and inferred the pathways involved. We found polygenic associations of SCZ with glucose metabolism abnormalities, adverse adipokine profiles, increased wait-hip ratio and raised visceral adiposity. However, BMI showed inverse genetic correlation and polygenic link with SCZ. On the other hand, we observed polygenic associations with an overall favorable CM profile in BD. MR analysis showed that SCZ may be causally linked to raised triglyceride and that lower fasting glucose may be linked to BD; otherwise MR did not reveal other significant causal relationships in general. We also identified numerous SNPs and pathways shared between SCZ/BD with cardiometabolic traits, some of which are related to inflammation or the immune system. In conclusion, SCZ patients may be genetically associated with several CM abnormalities independent of medication side-effects, and proper surveillance and management of CV risk factors may be required from the onset of the disease. On the other hand, CM abnormalities in BD are more likely to be secondary.