Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia, Bipolar Disorder, and Depression in the VA Health Care System

BackgroundSerious mental illnesses, including schizophrenia, bipolar disorder and depression are heritable, highly multifactorial disorders and major causes of disability worldwide. Polygenic risk scores (PRS) aggregate variants identified from genome-wide association studies (GWAS) into individual-level estimates of liability, and are a promising tool for clinical risk stratification. MethodsBy leveraging the VAs extensive electronic health record (EHR) and a cohort of 9,378 individuals with confirmed diagnoses of schizophrenia or bipolar I disorder, we validated automated case-control assignments based on ICD-9/10 codes, and benchmarked the performance of current PRS for schizophrenia, bipolar disorder, and major depression in 400,000 Million Veteran Program (MVP) participants. We explored broader relationships between PRS and 1,650 disease categories via phenome-wide association studies (PheWAS). Finally, we applied genomic structural equation modeling (gSEM) to derive novel PRS indexing common and disorder-specific latent genetic factors. FindingsAmong 3,953 and 5,425 individuals with diagnoses of schizophrenia or bipolar disorder type I that were confirmed by structured clinical interviews, 95% were correctly identified using ICD-9/10 codes (2 or more). Current PRS were robustly associated with case status in European (p<10-254) and African (p<10-5) participants and were higher among more frequently hospitalized patients (p<10-4). PheWAS confirmed previous associations among higher neuropsychiatric PRS and elevated risk for psychiatric and physical health problems and extended these findings to African Americans. InterpretationUsing diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRS, we demonstrated the validity of an EHR-based phenotyping approach in US veterans, highlighting the potential of PRS for disentangling biological and mediated pleiotropy. FundingDepartment of Veterans Affairs Cooperative Studies Program (CSP) #572; Million Veteran Program (MVP-000, MVP-006); Office of Research and Development, Department of Veterans Affairs.