Penetrance and pleiotropy of polygenic risk scores for schizophrenia in 106,160 patients across four health care systems

Amanda B. Zheutlin, Jessica Dennis, Richard Karlsson Linnér, Arden Moscati, Nicole Restrepo, Peter Straub, Douglas Ruderfer, Victor M. Castro, Chia Yen Chen, Tian Ge, Laura M. Huckins, Alexander Charney, H. Lester Kirchner, Eli A. Stahl, Christopher F. Chabris, Lea K. Davis, Jordan W. Smoller

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)846-855
Number of pages10
JournalAmerican Journal of Psychiatry
Volume176
Issue number10
Early online date16 Aug 2019
DOIs
Publication statusPublished - 1 Oct 2019

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Penetrance
Schizophrenia
Delivery of Health Care
Genetic Pleiotropy
Electronic Health Records
Personality Disorders
Memory Disorders
Nervous System Diseases
Psychotic Disorders
Substance-Related Disorders
Psychiatry
Meta-Analysis
Anxiety
Obesity

Cite this

Zheutlin, Amanda B. ; Dennis, Jessica ; Linnér, Richard Karlsson ; Moscati, Arden ; Restrepo, Nicole ; Straub, Peter ; Ruderfer, Douglas ; Castro, Victor M. ; Chen, Chia Yen ; Ge, Tian ; Huckins, Laura M. ; Charney, Alexander ; Kirchner, H. Lester ; Stahl, Eli A. ; Chabris, Christopher F. ; Davis, Lea K. ; Smoller, Jordan W. / Penetrance and pleiotropy of polygenic risk scores for schizophrenia in 106,160 patients across four health care systems. In: American Journal of Psychiatry. 2019 ; Vol. 176, No. 10. pp. 846-855.
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title = "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.",
author = "Zheutlin, {Amanda B.} and Jessica Dennis and Linn{\'e}r, {Richard Karlsson} and Arden Moscati and Nicole Restrepo and Peter Straub and Douglas Ruderfer and Castro, {Victor M.} and Chen, {Chia Yen} and Tian Ge and Huckins, {Laura M.} and Alexander Charney and Kirchner, {H. Lester} and Stahl, {Eli A.} and Chabris, {Christopher F.} and Davis, {Lea K.} and Smoller, {Jordan W.}",
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Zheutlin, AB, Dennis, J, Linnér, RK, Moscati, A, Restrepo, N, Straub, P, Ruderfer, D, Castro, VM, Chen, CY, Ge, T, Huckins, LM, Charney, A, Kirchner, HL, Stahl, EA, Chabris, CF, Davis, LK & Smoller, JW 2019, 'Penetrance and pleiotropy of polygenic risk scores for schizophrenia in 106,160 patients across four health care systems' American Journal of Psychiatry, vol. 176, no. 10, pp. 846-855. https://doi.org/10.1176/appi.ajp.2019.18091085

Penetrance and pleiotropy of polygenic risk scores for schizophrenia in 106,160 patients across four health care systems. / Zheutlin, Amanda B.; Dennis, Jessica; Linnér, Richard Karlsson; Moscati, Arden; Restrepo, Nicole; Straub, Peter; Ruderfer, Douglas; Castro, Victor M.; Chen, Chia Yen; Ge, Tian; Huckins, Laura M.; Charney, Alexander; Kirchner, H. Lester; Stahl, Eli A.; Chabris, Christopher F.; Davis, Lea K.; Smoller, Jordan W.

In: American Journal of Psychiatry, Vol. 176, No. 10, 01.10.2019, p. 846-855.

Research output: Contribution to JournalArticleAcademicpeer-review

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T1 - Penetrance and pleiotropy of polygenic risk scores for schizophrenia in 106,160 patients across four health care systems

AU - Zheutlin, Amanda B.

AU - Dennis, Jessica

AU - Linnér, Richard Karlsson

AU - Moscati, Arden

AU - Restrepo, Nicole

AU - Straub, Peter

AU - Ruderfer, Douglas

AU - Castro, Victor M.

AU - Chen, Chia Yen

AU - Ge, Tian

AU - Huckins, Laura M.

AU - Charney, Alexander

AU - Kirchner, H. Lester

AU - Stahl, Eli A.

AU - Chabris, Christopher F.

AU - Davis, Lea K.

AU - Smoller, Jordan W.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

AB - 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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DO - 10.1176/appi.ajp.2019.18091085

M3 - Article

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SP - 846

EP - 855

JO - American Journal of Psychiatry

JF - American Journal of Psychiatry

SN - 0002-953X

IS - 10

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