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[Preprint]. 2023 Jul 11:2023.03.22.23286865.
doi: 10.1101/2023.03.22.23286865.

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

Peter B Barr  1   2   3   4 , Tim B Bigdeli  1   2   3   4 , Jacquelyn L Meyers  1   2   3   4 , Roseann E Peterson  1   2   3 , Sandra Sanchez-Roige  5   6 , Travis T Mallard  7   8 , Danielle M Dick  9   10 , K Paige Harden  11   12 , Anna Wilkinson  13   14   15 , David P Graham  13   16 , David A Nielsen  13   16 , Alan Swann  13   16 , Rachele K Lipsky  13   16 , Thomas Kosten  13   16 , Mihaela Aslan  17   18 , Philip D Harvey  19   20 , Nathan A Kimbrel  21   22   23 , Jean C Beckham  21   22   23
Affiliations

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

Peter B Barr et al. medRxiv. .

Update in

  • Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort.
    Barr PB, Bigdeli TB, Meyers JL, Peterson RE, Sanchez-Roige S, Mallard TT, Dick DM, Harden KP, Wilkinson A, Graham DP, Nielsen DA, Swann AC, Lipsky RK, Kosten TR, Aslan M, Harvey PD, Kimbrel NA, Beckham JC; Million Veteran Program (MVP)Cooperative Studies Program (CSP) #572. Barr PB, et al. JAMA Psychiatry. 2024 Feb 1;81(2):188-197. doi: 10.1001/jamapsychiatry.2023.4141. JAMA Psychiatry. 2024. PMID: 37938835 Free PMC article.

Abstract

Background: Many psychiatric outcomes are thought to share a common etiological pathway reflecting behavioral disinhibition, generally referred to as externalizing disorders (EXT). Recent genome-wide association studies (GWAS) have demonstrated the overlap between EXT and important aspects of veterans' health, such as suicide-related behaviors, substance use disorders, and other medical conditions.

Methods: We conducted a series of phenome-wide association studies (PheWAS) of polygenic scores (PGS) for EXT, and comorbid psychiatric problems (depression, schizophrenia, and suicide attempt) in an ancestrally diverse cohort of U.S. veterans (N = 560,824), using diagnostic codes from electronic health records. We conducted ancestry-specific PheWASs of EXT PGS in the European, African, and Hispanic/Latin American ancestries. To determine if associations were driven by risk for other comorbid problems, we performed a conditional PheWAS, covarying for comorbid psychiatric problems (European ancestries only). Lastly, to adjust for unmeasured confounders we performed a within-family analysis of significant associations from the main PheWAS in full-siblings (N = 12,127, European ancestries only).

Results: The EXT PGS was associated with 619 outcomes across all bodily systems, of which, 188 were independent of risk for comorbid problems of PGS. Effect sizes ranged from 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%) and 26 (4.5%) were significant in the African and Hispanic/Latin American results, respectively. Within-family analyses uncovered robust associations between EXT and consequences of substance use disorders, including liver disease, chronic airway obstruction, and viral hepatitis C.

Conclusion: Our results demonstrate a shared polygenic basis of EXT across populations of diverse ancestries and independent of risk for other psychiatric problems. The strongest associations with EXT were for diagnoses related to substance use disorders and their sequelae. Overall, we highlight the potential negative consequences of EXT for health and functioning in the US veteran population.

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Figures

Figure 1:
Figure 1:. PheWAS of Externalizing Polygenic Risk in MVP.
PheWAS associations with EXT PGS in veterans of the primarily European ancestries (N = 406, 254). Panel A presents the box plots of effect sizes (odds ratios, OR) for the 619 (out of 1,652) significant PheWAS associations below the Bonferroni corrected p-value threshold (p < 7.57*10−6). Panel B presents an upset plot of overlap between phenome wide significant associations (p < 7.57*10−6) across all four PGS (EXT, DEP, SCZ, and SUI).
Figure 2:
Figure 2:. Multi-Ancestry Results for Externalizing Polygenic Risk in MVP.
Overlap in associations across European (EUR), African (AFR), and Hispanic/Latin American (HIS) ancestries. Panel A present the proportion of PGS 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. Panel B presents selected associations and corresponding effect sizes (odds ratios, OR) of EXT PGS associations that replicated in either African or Hispanic/Latin American ancestry groups.
Figure 3:
Figure 3:. Associations between EXT PGS and Selected Phecodes Accounting for DEP, SCZ, and SUI PGS.
Panel A presents selected associations and their corresponding effect sizes from conditional PheWAS (EXT + DEP, SCZ, and SUI PGS) in veterans of primarily European ancestries (N = 406, 254) compared to models with the EXT PGS only (marginal). Panel B presents 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:
Figure 4:. Change in Effect Sizes for EXT PGS 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 standard errors) and family fixed effects models. All associations significant after correcting for a false discovery rate (FDR) of 5%.
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