Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia in 106,160 Patients Across Four Health Care Systems

Abstract

Objective: Individuals at high risk for schizophrenia may benefit from early intervention, but few validated risk predictors are available. Genetic profiling is one approach to risk stratification that has been extensively validated in research cohorts. The authors sought to test the utility of this approach in clinical settings and to evaluate the broader health consequences of high genetic risk for schizophrenia.

Methods: The authors used electronic health records for 106,160 patients from four health care systems to evaluate the penetrance and pleiotropy of genetic risk for schizophrenia. Polygenic risk scores (PRSs) for schizophrenia were calculated from summary statistics and tested for association with 1,359 disease categories, including schizophrenia and psychosis, in phenome-wide association studies. Effects were combined through meta-analysis across sites.

Results: PRSs were robustly associated with schizophrenia (odds ratio per standard deviation increase in PRS, 1.55; 95% CI=1.4, 1.7), and patients in the highest risk decile of the PRS distribution had up to 4.6-fold higher odds of schizophrenia compared with those in the bottom decile (95% CI=2.9, 7.3). PRSs were also positively associated with other phenotypes, including anxiety, mood, substance use, neurological, and personality disorders, as well as suicidal behavior, memory loss, and urinary syndromes; they were inversely related to obesity.

Conclusions: The study demonstrates that an available measure of genetic risk for schizophrenia is robustly associated with schizophrenia in health care settings and has pleiotropic effects on related psychiatric disorders as well as other medical syndromes. The results provide an initial indication of the opportunities and limitations that may arise with the future application of PRS testing in health care systems.

Keywords: Chronic Psychiatric Illness; Cognitive Neuroscience; Genetics; Schizophrenia.

FIGURE 1.. Schizophrenia case prevalence by polygenic risk score (PRS) decile among patients in four health care systems^a

^a Schizophrenia (phecode 295.1) case prevalence by site and across all health care systems was plotted by schizophrenia PRS decile for both PRS methods. GHS=Geisinger Health System; LD=linkage disequilibrium; MSSM=Mount Sinai School of Medicine; PHS=Partners HealthCare System; VUMC=Vanderbilt University Medical Center.

FIGURE 2.. Odds ratios for top schizophrenia polygenic risk score (PRS) decile among patients in four health care systems^a

^a Odds ratios for phenotypes significant in LD-pruned PRS phenome-wide association study meta-analysis were plotted for the top PRS decile with reference to both the remaining 90% and the bottom decile. The vertical line (odds ratio=1) reflects no change in risk. Error bars indicate 95% confidence intervals. LD=linkage disequilibrium.

FIGURE 3.. Schizophrenia polygenic risk score (PRS) phenome-wide association study meta-analysis across four health care systems^a

^a The figure is a Manhattan plot for phenome-wide association with LD-pruned schizophrenia PRSs meta-analyzed across four health care systems (1,359 phenotypes; 106,160 patients). The horizontal axis indicates phenotype (grouped by broad disease category) and the vertical axis indicates the significance (–log10 p; two-tailed) of the association derived by logistic regression. The horizontal red line within the graph indicates phenome-wide-level significance (p=3.7×10⁻⁵) using Bonferroni correction, and all phenotypes that pass this threshold are labeled. All significant effects were positive (i.e., higher polygenic risk scores resulted in higher incidence of the phenotype), with three exceptions: morbid obesity, obesity, and synovitis and tenosynovitis. LD=linkage disequilibrium.