Oxytocin pathway polygenic risk scores for severe mental disorder and metabolic phenotypes in the UK Biobank

Oxytocin is a neuromodulator and hormone that is typically associated with social cognition and behavior. In light of its purported effects on social cognition and behavior, research has investigated its potential as a treatment for psychiatric illnesses characterised by social dysfunction, such as schizophrenia and bipolar disorder. While the results of these trials have been mixed, more recent evidence suggests that the oxytocin system is also linked with cardiometabolic conditions for which individuals with severe mental disorders are at a higher risk for developing. To investigate whether the oxytocin system plays a pleiotropic role in the aetiology of severe mental illness and cardiometabolic conditions, we explored oxytocin’s role in the shared genetic liability of schizophrenia, bipolar disorder, type 2 diabetes and several phenotypes linked with cardiovascular disease and type 2 diabetes risk using a polygenic pathway-specific approach. Analysis of a large sample with 488,377 individuals (UK Biobank) revealed statistically significant associations across the range of phenotypes analysed. By comparing these effects to those of polygenic scores calculated from 100 random gene-sets, we also demonstrated the specificity of many of these significant results. Altogether, our results suggest that the shared effect of oxytocin system dysfunction could help explain the co-occurrence of social and cardiometabolic dysfunction in severe mental illnesses.