Associations Between Major Psychiatric Disorder Polygenic Risk Scores and Blood-Based Markers in UK Biobank

Background Major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD) have both shared and discrete genetic risk factors and abnormalities in blood-based measures of inflammation and blood-brain barrier (BBB) permeability. The relationships between such genetic architectures and blood-based markers are however unclear. We investigated relationships between polygenic risk scores for these disorders and peripheral biomarkers in the UK Biobank cohort. Methods We calculated polygenic risk scores (PRS) for samples of n = 367,329 (MDD PRS), n = 366,465 (SCZ PRS), and n = 366,383 (BD PRS) individuals from the UK Biobank cohort. We examined associations between each disorder PRS and 62 blood markers, using two generalized linear regression models: ‘minimally adjusted’ controlling for variables including age and sex, and ‘fully adjusted’ including additional lifestyle covariates such as alcohol and smoking status. Results 12/62, 13/62 and 9/62 peripheral markers were significantly associated with MDD, SCZ and BD PRS respectively for both models. Most associations were disorder PRS-specific, including several immune-related markers for MDD and SCZ. We also identified several BBB-permeable marker associations, including vitamin D for all three disorder PRS, IGF-1 and triglycerides for MDD PRS, testosterone for SCZ PRS, and HDL cholesterol for BD PRS. Conclusions This study suggests that MDD, SCZ and BD have shared and distinct peripheral markers associated with disorder-specific genetic risk. The results implicate BBB permeability disruptions in all three disorders and inflammatory dysfunction in MDD and SCZ, and enrich our understanding of potential underlying pathophysiological mechanisms in major psychiatric disorders.