Specificity of Psychiatric Polygenic Risk Scores and Their Effects on Associated Risk Phenotypes

Abstract

BackgroundPolygenic risk scores (PRSs) are indices of genetic liability for illness, but their clinical utility for predicting risk for a specific psychiatric disorder is limited. Genetic overlap among disorders and their effects on allied phenotypes may be a possible explanation, but this has been difficult to quantify given focus on singular disorders and/or allied phenotypes. MethodsWe constructed PRSs for 5 psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention-deficit/hyperactivity disorder) and 3 nonpsychiatric control traits (height, type II diabetes, irritable bowel disease) in the UK Biobank (N = 31,616) and quantified associations between PRSs and phenotypes allied with mental illness: behavioral (symptoms, cognition, trauma) and brain measures from magnetic resonance imaging. We then evaluated the extent of specificity among PRSs and their effects on these allied phenotypes. ResultsCorrelations among psychiatric PRSs replicated previous work, with overlap between schizophrenia and bipolar disorder, which was distinct from overlap between autism spectrum disorder and attention-deficit/hyperactivity disorder; overlap between psychiatric and control PRSs was minimal. There was, however, substantial overlap of PRS effects on allied phenotypes among psychiatric disorders and among psychiatric disorders and control traits, where the extent and pattern of overlap was phenotype specific. ConclusionsResults show that genetic distinctions between psychiatric disorders and between psychiatric disorders and control traits exist, but this does not extend to their effects on allied phenotypes. Although overlap can be informative, work is needed to construct PRSs that will function at the level of specificity needed for clinical application.