Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort
Authors: Barr Peter B. , Bigdeli Tim B. , Meyers Jacquelyn L. , Peterson Roseann E. , Sanchez-Roige Sandra , Mallard Travis T. , Dick Danielle M. , Harden K. Paige , Wilkinson Anna , Graham David P. , Nielsen David A. , Swann Alan C. , Lipsky Rachele K. , Kosten Thomas R. , Aslan Mihaela , Harvey Philip D. , Kimbrel Nathan A. , Beckham Jean C. ,   Million Veteran Program (MVP)Cooperative Studies Program (CSP) #572, 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: November 2023

ImportanceMany psychiatric outcomes share a common etiologic pathway reflecting behavioral disinhibition, generally referred to as externalizing (EXT) disorders. Recent genome-wide association studies (GWASs) have demonstrated the overlap between EXT disorders and important aspects of veterans’ health, such as suicide-related behaviors and substance use disorders (SUDs).ObjectiveTo explore correlates of risk for EXT disorders within the Veterans Health Administration (VA) Million Veteran Program (MVP).Design, Setting, and ParticipantsA series of phenome-wide association studies (PheWASs) of polygenic risk scores (PGSs) for EXT disorders was conducted using electronic health records. First, ancestry-specific PheWASs of EXT PGSs were conducted in the African, European, and Hispanic or Latin American ancestries. Next, a conditional PheWAS, covarying for PGSs of comorbid psychiatric problems (depression, schizophrenia, and suicide attempt; European ancestries only), was performed. Lastly, to adjust for unmeasured confounders, a within-family analysis of significant associations from the main PheWAS was performed in full siblings (European ancestries only). This study included the electronic health record data from US veterans from VA health care centers enrolled in MVP. Analyses took place from February 2022 to August 2023 covering a period from October 1999 to January 2020.ExposuresPGSs for EXT, depression, schizophrenia, and suicide attempt.Main Outcomes and MeasuresPhecodes for diagnoses derived from theInternational Statistical Classification of Diseases,NinthandTenth Revisions,Clinical Modification, codes from electronic health records.ResultsWithin the MVP (560 824 patients; mean [SD] age, 67.9 [14.3] years; 512 593 male [91.4%]), the EXT PGS was associated with 619 outcomes, of which 188 were independent of risk for comorbid problems or PGSs (from odds ratio [OR], 1.02; 95% CI, 1.01-1.03 for overweight/obesity to OR, 1.44; 95% CI, 1.42-1.47 for viral hepatitis C). Of the significant outcomes, 73 (11.9%) were significant in the African results and 26 (4.5%) were significant in the Hispanic or Latin American results. Within-family analyses uncovered robust associations between EXT PGS and consequences of SUDs, including liver disease, chronic airway obstruction, and viral hepatitis C.Conclusions and RelevanceResults of this cohort study suggest a shared polygenic basis of EXT disorders, independent of risk for other psychiatric problems. In addition, this study found associations between EXT PGS and diagnoses related to SUDs and their sequelae. Overall, this study highlighted the potential negative consequences of EXT disorders for health and functioning in the US veteran population.