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Penetrance and pleiotropy of polygenic risk scores for schizophrenia in 90,000 patients across three healthcare systems

Amanda B Zheutlin, Jessica Dennis, Nicole Restrepo, Peter Straub, Douglas Ruderfer, Victor M Castro, Chia-Yen Chen, H. Lester Kirchner, Christopher F. Chabris, Lea K Davis, Jordan W Smoller
doi: https://doi.org/10.1101/421164
Amanda B Zheutlin
1Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA
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Jessica Dennis
2Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
3Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN
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Nicole Restrepo
4Department of Biomedical & Translational Informatics, Geisinger, Rockville, MD
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Peter Straub
2Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
3Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN
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Douglas Ruderfer
2Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
3Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN
5Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN
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Victor M Castro
6Research Information Science and Computing, Partners HealthCare, Somerville, MA
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Chia-Yen Chen
1Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA
7Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA
8Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA
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H. Lester Kirchner
4Department of Biomedical & Translational Informatics, Geisinger, Rockville, MD
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Christopher F. Chabris
9Autism and Developmental Medicine Institute, Geisinger, Lewisburg, PA
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Lea K Davis
2Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
3Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN
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Jordan W Smoller
1Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA
7Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA
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Abstract

BACKGROUND Individuals at high risk 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, but its utility in clinical settings remains largely unexplored. Moreover, the broad health consequences of a high genetic risk of schizophrenia are poorly understood, despite being highly relevant to treatment decisions.

METHODS We used electronic health records of 91,980 patients from three large healthcare systems to evaluate the penetrance and pleiotropy of genetic risk for schizophrenia. Polygenic risk scores (PRSs) for schizophrenia were calculated from meta-analysis summary statistics and tested for association with schizophrenia diagnostic codes and 1338 code-defined disease categories in a phenome-wide association study. Effect estimates were meta-analyzed across sites, and follow-up analyses evaluated the effect of a schizophrenia diagnosis.

RESULTS PRSs were robustly associated with schizophrenia (odds ratio per standard deviation increase in PRS = 1.65 [95% confidence interval (CI), 1.5-1.8], p = 1.25 × 10-16) and patients in the highest risk decile of the PRS distribution had a four-fold increased odds of schizophrenia compared to those in the bottom decile (95% CI, 2.4-6.5, p = 4.43 × 10-8). PRSs were also associated with other psychiatric phenotypes, including anxiety disorders, bipolar disorder, depression, substance use disorders, personality disorders, and suicidal behavior. Non-psychiatric associations included heart palpitations, urinary syndromes, obesity, and nonspecific somatic symptoms. Most associations remained significant when conditioning on a diagnosis of schizophrenia, indicating genetic pleiotropy.

CONCLUSIONS We demonstrate that an available measure of genetic risk for schizophrenia is robustly associated with schizophrenia in healthcare settings and has pleiotropic effects on related psychiatric disorders as well as other medical symptoms and syndromes. Our results provide an initial indication of the opportunities and limitations that may arise with the future application of PRS testing in healthcare systems.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 18, 2018.
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Penetrance and pleiotropy of polygenic risk scores for schizophrenia in 90,000 patients across three healthcare systems
Amanda B Zheutlin, Jessica Dennis, Nicole Restrepo, Peter Straub, Douglas Ruderfer, Victor M Castro, Chia-Yen Chen, H. Lester Kirchner, Christopher F. Chabris, Lea K Davis, Jordan W Smoller
bioRxiv 421164; doi: https://doi.org/10.1101/421164
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Penetrance and pleiotropy of polygenic risk scores for schizophrenia in 90,000 patients across three healthcare systems
Amanda B Zheutlin, Jessica Dennis, Nicole Restrepo, Peter Straub, Douglas Ruderfer, Victor M Castro, Chia-Yen Chen, H. Lester Kirchner, Christopher F. Chabris, Lea K Davis, Jordan W Smoller
bioRxiv 421164; doi: https://doi.org/10.1101/421164

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