Dataset Information

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

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.

SUBMITTER: Barr PB

PROVIDER: S-EPMC10081391 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Barr Peter B PB Bigdeli Tim B TB Meyers Jacquelyn L JL Peterson Roseann E RE Sanchez-Roige Sandra S Mallard Travis T TT Dick Danielle M DM Paige Harden K K Wilkinson Anna A Graham David P DP Nielsen David A DA Swann Alan A Lipsky Rachele K RK Kosten Thomas T Aslan Mihaela M Harvey Philip D PD Kimbrel Nathan A NA Beckham Jean C JC

medRxiv : the preprint server for health sciences 20230711

<h4>Background</h4>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.<h4>Methods</h4>We conducted a series of phenome-wide association studies (PheWAS) of polyge ...[more]

PMID: 37034805

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Project description:Increasing rates of human papillomavirus (HPV)-driven oropharyngeal cancer (OPC) have largely offset declines in tobacco-associated head and neck squamous cell carcinoma (HNSCC) at non-OPC sites. Host immunity is an important modulator of HPV infection, persistence, and clearance, and also of immune evasion in both virally- and nonvirally-driven cancers. However, the association between collective known cancer-related immune gene variants and HNSCC susceptibility has not been fully characterized. Here, we conducted a genetic association study in the multiethnic Veterans Affairs Million Veteran Program cohort, evaluating 16,050 variants in 1,576 immune genes in 4,012 HNSCC cases (OPC = 1,823; non-OPC = 2,189) and 16,048 matched controls. Significant polymorphisms were further examined in a non-Hispanic white (NHW) validation cohort (OPC = 1,206; non-OPC = 955; controls = 4,507). For overall HNSCC susceptibility in NHWs, we discovered and validated a novel 9q31.1 SMC2 association and replicated the known 6p21.32 HLA-DQ-DR association. Six loci/genes for overall HNSCC susceptibility were selectively enriched in African-Americans (6p21.32 HLA-G, 9q21.33 GAS1, 11q12.2 CD6, 11q23.2 NCAM1/CD56, 17p13.1 CD68, 18q22.2 SOCS6); all 6 genes function in antigen-presenting regulation and T-cell activation. Two additional loci (10q26 DMBT1, 15q22.2 TPM1) were uncovered for non-OPC susceptibility, and three loci (11q24 CRTAM, 16q21 CDH5, 18q12.1 CDH2) were identified for HPV-positive OPC susceptibility. This study underscores the role of immune gene variants in modulating susceptibility for both HPV-driven and non-HPV-driven HNSCC. Additional large studies, particularly in racially diverse populations, are needed to further validate the associations and to help elucidate other potential immune factors and mechanisms that may underlie HNSCC risk.SignificanceSeveral inherited variations in immune system genes are significantly associated with susceptibility to head and neck cancer, which could help improve personalized cancer risk estimates.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

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