Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia, Bipolar Disorder, and Depression Among Adults in the US Veterans Affairs Health Care System

Abstract

for the Cooperative Studies Program (CSP) #572 and Million Veteran Program (MVP)IMPORTANCE Serious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide.OBJECTIVE To benchmark the penetrance of current neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration health care system and to explore associations between PRS and broad categories of human disease via phenome-wide association studies.DESIGN, SETTING, AND PARTICIPANTS Extensive Veterans Health Administration's electronic health records were assessed from October 1999 to January 2021, and an embedded cohort of 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder were found. The performance of schizophrenia, bipolar disorder, and major depression PRSs were compared in participants of African or European ancestry in the Million Veteran Program (approximately 400 000 individuals), and associations between PRSs and 1650 disease categories based on ICD-9/10 billing codes were explored. Last, genomic structural equation modeling was applied to derive novel PRSs indexing common and disorder-specific genetic factors. Analysis took place from January 2021 to January 2022. MAIN OUTCOMES AND MEASURESDiagnoses based on in-person structured clinical interviews were compared with ICD-9/10 billing codes. PRSs were constructed using summary statistics from genome-wide association studies of schizophrenia, bipolar disorder, and major depression. RESULTSOf 707 299 enrolled study participants, 459 667 were genotyped at the time of writing; 84 806 were of broadly African ancestry (mean [SD] age, 58 [12.1] years) and 314 909 were of broadly European ancestry (mean [SD] age, 66.4 [13.5] years). Among 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder, 8962 (95.6%) were correctly identified using ICD-9/10 codes (2 or more). Among those of European ancestry, PRSs were robustly associated with having received a diagnosis of schizophrenia (odds ratio [OR], 1.81 [95% CI, 1.76-1.87]; P < 10 −257 ) or bipolar disorder (OR, 1.42 [95% CI,; P < 10 −295 ). Corresponding effect sizes in participants of African ancestry were considerably smaller for schizophrenia (OR, 1.35 [95% CI,; P < 10 −38 ) and bipolar disorder (OR, 1.16 [95% CI,; P < 10 −10 ). Neuropsychiatric PRSs were associated with increased risk for a range of psychiatric and physical health problems. CONCLUSIONS AND RELEVANCEUsing diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRSs, the validity of an electronic health records-based phenotyping approach in US veterans was demonstrated, highlighting the potential of PRSs for disentangling biological and mediated pleiotropy.

Detecting and Adjusting for Hidden Biases due to Phenotype Misclassification in Genome-Wide Association Studies

“…First, we consider effective dilution between two separate GWA studies using the presence of one (1; lenient) or at least two (2+; strict) phecode counts for bipolar disorder in the Million Veteran Program (MVP), leveraging non-overlapping patients (and controls) for each analysis. As expected from our prior work 19 (Fig. 3, Tables S2, S3).…”

Polygenic risk scores: An overview from bench to bedside for personalised medicine

“…A study of 106,160 patients not only showed a strong association with schizophrenia but also with anxiety, mood, substance use, personality disorders and suicidal behaviour (Zheutlin et al, 2019). Similarly, in a study in the United States Veterans Affairs Health Care System in patients with schizophrenia, bipolar disorder and depression, higher PRSs were associated with higher likelihood of mental and physical health diagnoses, although the effect size was lower in African ancestry individuals than in those of European ancestry (Bigdeli et al, 2022). A phenome-wide analysis of UK Biobank participants has shown that highly pleiotropic variants corresponded to ubiquitously expressed genes important for extracellular matrix, regulation of cell growth and signalling pathways (Shikov et al, 2020).…”

Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort

“…This hypothesis-free approach, referred to as a phenome-wide association study (PheWAS), can aid in understanding pleiotropic effects. Recent PheWASs using PGSs for other psychiatric problems (eg, schizophrenia, bipolar disorder, and depression) have identified widespread associations between PGSs and a host of psychiatric and other medical diagnoses …”