Amanda B Zheutlin1, Jessica Dennis1, Richard Karlsson Linnér1, Arden Moscati1, Nicole Restrepo1, Peter Straub1, Douglas Ruderfer1, Victor M Castro1, Chia-Yen Chen1, Tian Ge1, Laura M Huckins1, Alexander Charney1, H Lester Kirchner1, Eli A Stahl1, Christopher F Chabris1, Lea K Davis1, Jordan W Smoller1. 1. Psychiatric and Neurodevelopmental Genetics Unit (Zheutlin, Chen, Ge, Smoller) and Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Chen); Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Mass. (Zheutlin, Chen, Stahl, Smoller); Division of Genetic Medicine, Department of Medicine (Dennis, Straub, Ruderfer, Davis), Vanderbilt Genetics Institute (Dennis, Straub, Ruderfer, Davis), and Department of Biomedical Informatics (Ruderfer), Vanderbilt University Medical Center, Nashville; Department of Economics, School of Business and Economics, Vrije Universiteit Amsterdam, Amsterdam (Karlsson Linnér); Autism and Developmental Medicine Institute, Geisinger, Lewisburg, Pa. (Karlsson Linnér, Chabris); Charles Bronfman Institute for Personalized Medicine (Moscati), Pamela Sklar Division of Psychiatric Genomics (Huckins, Charney, Stahl), and Department of Genetics and Genomic Sciences (Huckins, Charney, Stahl, ), Icahn School of Medicine at Mount Sinai, New York; Department of Biomedical and Translational Informatics, Geisinger, Rockville, Md. (Restrepo, Kirchner); Research Information Science and Computing, Partners HealthCare, Somerville, Mass. (Castro).
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.
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.
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