Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort

Abstract

Importance: Many 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).

Objective: To explore correlates of risk for EXT disorders within the Veterans Health Administration (VA) Million Veteran Program (MVP).

Design, setting, and participants: A 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.

Exposures: PGSs for EXT, depression, schizophrenia, and suicide attempt.

Main outcomes and measures: Phecodes for diagnoses derived from the International Statistical Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification, codes from electronic health records.

Results: Within 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 relevance: Results 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.

Figure 1.. Phenome-Wide Association Study (PheWAS) of Externalizing Polygenic Risk in the Million Veteran Program (MVP)

PheWAS associations with externalizing (EXT) disorders polygenic risk scores (PGSs) in veterans of the primarily European ancestries (N = 406, 255). Phecodes are grouped into 17 categories: infectious diseases, neoplasms, endocrine/metabolic, hematopoietic, mental disorders, neurological, sense organs, circulatory system, respiratory, digestive, genitourinary, pregnancy complications, dermatologic, musculoskeletal, congenital anomalies, symptoms, and injuries & poisonings. A, Box plots of effect sizes (odds ratios [ORs]) for the 619 of 1652 significant PheWAS associations below the Bonferroni corrected P value threshold (P < 7.57 × 10⁻⁶). B, Upset plot of overlap between phenome-wide significant associations (P < 7.57 × 10⁻⁶) across all 4 PGSs (EXT, depression, schizophrenia, and suicide attempt).

Figure 2.. Multiancestry Results for Externalizing (EXT) Disorder Polygenic Risk in the Million Veteran Program (MVP)

Overlap in associations across African (AFR), European (EUR), and Hispanic or Latin American (HIS) ancestries. A, Proportion of polygenic risk scores (PGSs) identified in EUR ancestries that were significant in the AFR and HIS groupings by phecode domain. Numbers in parentheses represent the total number of significant associations in EUR, per phecode domain. B, Selected associations and corresponding effect sizes (odds ratios [ORs]) of EXT PGS associations that replicated in either AFR or HIS ancestry groups. HARE indicates harmonized ancestry and race-ethnicity.

Figure 3.. Associations Between Externalizing Disorder (EXT) Polygenic Risk Score (PGS) and Selected Phecodes Accounting for Depression, Schizophrenia, and Suicide Attempt PGSs

A, Selected associations and their corresponding effect sizes from conditional phenome-wide association studies (PheWASs; EXT + depression, schizophrenia, and suicide attempt PGSs) in veterans of primarily European ancestries (N = 406 255) compared with models with the EXT PGS only (marginal). B, Box plots for the effect sizes from the 619 significant associations identified in the main PheWAS in (1) the PheWAS of EXT PGS only; (2) the PheWAS of EXT and other PGSs; and (3) the PheWAS of EXT, other PGSs, and the total comorbidity score.

Figure 4.. Change in Effect Sizes for Externalizing Disorder (EXT) Polygenic Risk Scores (PGSs) in Within-Family Models

Change in effect sizes for significant associations in a sample of related veterans of primarily European ancestries (N = 12 127). Estimates represent the change between ordinary least squares models (with clustered SEs) and family fixed-effects models. All associations significant after correcting for a false discovery rate (FDR) of 5%. OLS indicates ordinary least squares.