Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia, Bipolar Disorder, and Depression Among Adults in the US Veterans Affairs Health Care System
Authors: 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 ,   Cooperative Studies Program (CSP) #572 and Million Veteran Program (MVP), Aslan Mihaela , Antonelli M , de Asis M , Bauer MS , Brophy Mary , Concato John , Cunningham F , Freedman R , Gaziano Michael , Gleason Theresa , Harvey Philip , Huang Grant , Kelsoe J , Kosten Thomas , Lehner T , Lohr JB , Marder SR , Miller P , O Leary Timothy , Patterson T , Peduzzi P , Przygodski Ronald , Siever Larry , Sklar P , Strakowski S , Zhao Hongyu , Fanous Ayman , Farwell W , Malhorta A , Mane S , Palacios P , Bigdeli Tim , Corsey M , Zaluda L , Johnson Juanita , Sueiro Melyssa , Cavaliere D , Jeanpaul V , Maffucci Alysia , Mancini L , Deen J , Muldoon G , Whitbourne Stacey , Canive J , Adamson L , Calais L , Fuldauer G , Kushner R , Toney G , Lackey M , Mank A , Mahdavi N , Villarreal G , Muly EC , Amin F , Dent M , Wold J , Fischer B , Elliott A , Felix C , Gill G , Parker PE , Logan C , McAlpine J , DeLisi LE , Reece SG , Hammer MB , Agbor-Tabie D , Goodson W , Aslam M , Grainger M , Richtand Neil , Rybalsky Alexander , Al Jurdi R , Boeckman E , Natividad T , Smith D , Stewart M , Torres S , Zhao Z , Mayeda A , Green A , Hofstetter J , Ngombu S , Scott MK , Strasburger A , Sumner J , Paschall G , Mucciarelli J , Owen R , Theus S , Tompkins D , Potkin SG , Reist C , Novin M , Khalaghizadeh S , Douyon Richard , Kumar Nita , Martinez Becky , Sponheim SR , Bender TL , Lucas HL , Lyon AM , Marggraf MP , Sorensen LH , Surerus CR , Sison C , Amato J , Johnson DR , Pagan-Howard N , Adler LA , Alerpin S , Leon T , Mattocks KM , Araeva N , Sullivan JC , Suppes T , Bratcher K , Drag L , Fischer EG , Fujitani L , Gill S , Grimm D , Hoblyn J , Nguyen T , Nikolaev E , Shere L , Relova R , Vicencio A , Yip M , Hurford I , Acheampong S , Carfagno G , Haas GL , Appelt C , Brown E , Chakraborty B , Kelly E , Klima G , Steinhauer S , Hurley RA , Belle R , Eknoyan D , Johnson K , Lamotte J , Granholm E , Bradshaw K , Holden J , Jones RH , Le T , Molina IG , Peyton M , Ruiz I , Sally L , Tapp A , Devroy S , Jain V , Kilzieh N , Maus L , Miller K , Pope H , Wood A , Meyer E , Givens P , Hicks PB , Justice S , McNair K , Pena JL , Tharp DF , Davis L , Ban M , Cheatum L , Darr P , Grayson W , Munford J , Whitfield B , Wilson E , Melnikoff SE , Schwartz BL , Tureson MA , D Souza D , Forselius K , Ranganathan M , Rispoli L , Sather M , Colling C , Haakenson C , Kruegar D , Muralidhar Sumitra , Ramoni Rachel , Breeling Jim , Chang Kyong-Mi , O Donnell Christopher , Tsao Philip , Moser Jennifer , Brewer Jessica , Warren Stuart , Argyres Dean , Stevens Brady , Humphries Donald , Do Nhan , Shayan Shahpoor , Nguyen Xuan-Mai , Pyarajan Saiju , Cho Kelly , Hauser Elizabeth , Sun Yan , Wilson Peter , McArdle Rachel , Dellitalia Louis , Harley John , Whittle Jeffrey 
Published: September 2022

ImportanceSerious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide.ObjectiveTo 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 ParticipantsExtensive 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 MeasuresDiagnoses 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.ResultsOf 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 &amp;lt; 10−257) or bipolar disorder (OR, 1.42 [95% CI, 1.39-1.44]; P &amp;lt; 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 &amp;lt; 10−38) and bipolar disorder (OR, 1.16 [95% CI, 1.11-1.12]; P &amp;lt; 10−10). Neuropsychiatric PRSs were associated with increased risk for a range of psychiatric and physical health problems.Conclusions and RelevanceUsing 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.