Tim B Bigdeli1,2,3, Georgios Voloudakis4,5,6, Peter B Barr1,2,3, Bryan R Gorman7, Giulio Genovese8,9, Roseann E Peterson1,2,3,10, David E Burstein4,5,6, Vlad I Velicu4,5,6, Yuli Li11,12, Rishab Gupta13, Manuel Mattheisen14,15,16, Simone Tomasi4,5,6, Nallakkandi Rajeevan11,12, Frederick Sayward11,12, Krishnan Radhakrishnan17, Sundar Natarajan1, Anil K Malhotra18,19,20, Yunling Shi7, Hongyu Zhao11,12, Thomas R Kosten21,22, John Concato12,23, Timothy J O'Leary24, Ronald Przygodzki24, Theresa Gleason24, Saiju Pyarajan7, Mary Brophy7,25, Grant D Huang24, Sumitra Muralidhar24, J Michael Gaziano7,9, Mihaela Aslan11,12, Ayman H Fanous26,27, Philip D Harvey28,29, Panos Roussos4,5,6. 1. VA New York Harbor Healthcare System, Brooklyn. 2. Institute for Genomics in Health, SUNY Downstate Health Sciences University, Brooklyn, New York. 3. Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, New York. 4. James J. Peters Veterans Affairs Medical Center, Bronx, New York. 5. Departments of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York. 6. Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York. 7. Massachusetts Area Veterans Epidemiology, Research, and Information Center (MAVERIC), Jamaica Plain. 8. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 9. Harvard Medical School, Boston, Massachusetts. 10. Department of Psychiatry, Virginia Commonwealth University, Richmond. 11. Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, Connecticut. 12. Yale University School of Medicine, New Haven, Connecticut. 13. Department of Psychiatry, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts. 14. Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada. 15. Department of Community Health, Dalhousie University, Halifax, Nova Scotia, Canada. 16. Department of Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada. 17. National Mental Health and Substance Use Policy Laboratory, Substance Abuse and Mental Health Services Administration, Rockville, Maryland. 18. Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, New York. 19. Division of Psychiatry Research, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York. 20. Department of Psychiatry, Hofstra Northwell School of Medicine, Hempstead, New York. 21. Michael E. DeBakey VA Medical Center, Houston, Texas. 22. Department of Psychiatry, Neuroscience, Pharmacology, and Immunology and Rheumatology, Baylor College of Medicine, Houston, Texas. 23. Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland. 24. Office of Research and Development, Veterans Health Administration, Washington, DC. 25. Boston University School of Medicine, Boston, Massachusetts. 26. Department of Psychiatry, University of Arizona College of Medicine-Phoenix, Phoenix. 27. Carl T. Hayden Veterans Affairs Medical Center, Phoenix, Arizona. 28. Bruce W. Carter Miami Veterans Affairs (VA) Medical Center, Miami, Florida. 29. University of Miami Miller School of Medicine, Miami, Florida.
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.
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.
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