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

Abstract

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 measures: Diagnoses 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.

Results: Of 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, 1.39-1.44]; P < 10-295). Corresponding effect sizes in participants of African ancestry were considerably smaller for schizophrenia (OR, 1.35 [95% CI, 1.29-1.42]; P < 10-38) and bipolar disorder (OR, 1.16 [95% CI, 1.11-1.12]; P < 10-10). Neuropsychiatric PRSs were associated with increased risk for a range of psychiatric and physical health problems.

Conclusions and relevance: Using 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.

Figure 1.. Prediction of Structured Clinical Interview for the DSM–Confirmed Diagnoses From Electronic Health Record–Based Criteria

For varying schizophrenia (A) and bipolar 1 disorder (B) case criteria displayed in the Table, sensitivity and specificity estimates for a split-half cross-validation experiment are displayed. In each panel, the dashed line indicates a random (50/50) prediction.

Figure 2.. Case Prevalence by Neuropsychiatric Polygenic Risk Score (PRS) Decile in the Million Veteran Program

For PRSs constructed from current Psychiatric Genomics Consortium summary statistics for schizophrenia, bipolar disorder, and major depression, the estimated prevalence of that diagnosis in each PRS decile is displayed separately for populations of African and European ancestries. Ascertained patients enrolled in Cooperative Studies Program #572 were excluded.

Figure 3.. Phenome-Wide Association Studies Results for Neuropsychiatric Polygenic Risk Scores

A, For significant results in phenome-wide association studies of schizophrenia and major depression polygenic risk scores, the distribution of effect sizes within each disease category is displayed as a boxplot. A null effect (ie, odds ratio, 1) is denoted as a dotted line. B, Effect sizes of Psychiatric Genomics Consortium schizophrenia loci on bipolar disorder (phecode 296.1), sensorineural hearing loss (phecode 389.1), osteoarthritis (phecode 740.1), and diabetes (phecode 250) in Million Veteran Program participants of European ancestry. A null effect is denoted as a dotted line. Labeled loci achieved genome-wide significance in tests of the target phenotype. NEC indicates not elsewhere classified.

Figure 4.. Association of Neuropsychiatric Polygenic Risk Scores (PRSs) With Psychotic and Affective Diagnoses

A, Loadings of a common factor on schizophrenia (SCZ), bipolar disorder (BIP), and major depression (MDD) results and residual variances corresponding to disorder-specific effects. B, Odds ratios per SD unit increase in PRS for selected diagnoses compared against a common set of controls; analogous results based on latent, disorder-specific PRS appear are plotted in lighter hues. Case assignments were hierarchical and nonoverlapping. DEP indicates depression; PGC, Psychiatric Genomics Consortium.