Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia, Bipolar Disorder, and Depression Among Adults in the US Veterans Affairs Health Care System

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 He...

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Veröffentlicht in:JAMA psychiatry (Chicago, Ill.) Ill.), 2022-11, Vol.79 (11), p.1092-1101
Hauptverfasser: Bigdeli, Tim B, Voloudakis, Georgios, Barr, Peter B, Gorman, Bryan R, Genovese, Giulio, Peterson, Roseann E, Burstein, David E, Velicu, Vlad I, Li, Yuli, Gupta, Rishab, Mattheisen, Manuel, Tomasi, Simone, Rajeevan, Nallakkandi, Sayward, Frederick, Radhakrishnan, Krishnan, Natarajan, Sundar, Malhotra, Anil K, Shi, Yunling, Zhao, Hongyu, Kosten, Thomas R, Concato, John, O’Leary, Timothy J, Przygodzki, Ronald, Gleason, Theresa, Pyarajan, Saiju, Brophy, Mary, Huang, Grant D, Muralidhar, Sumitra, Gaziano, J. Michael, Aslan, Mihaela, Fanous, Ayman H, Harvey, Philip D, Roussos, Panos
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Zusammenfassung: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 
ISSN:2168-622X
2168-6238
2168-6238
DOI:10.1001/jamapsychiatry.2022.2742