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 importance of EXT for aspects of veterans health, such as suicide-related behaviors, substance use disorders, and other medical conditions. To better understand how genetic risk for EXT is related to veterans health, we conducted a series of phenome-wide association studies (PheWAS) of polygenic scores (PGS) for EXT, and comorbid psychopathology (depression, schizophrenia, suicide attempt) in an ancestrally diverse cohort of U.S. veterans (Total N = 560,824), using diagnostic codes from electronic health records. First, to identify phenotypes associated with the EXT PGS, we conducted ancestry-specific PheWAS in the European, African, and Admixed American ancestries (separately). Second, to determine if associations were driven by risk for other comorbid psychiatric conditions, we performed a conditional PheWAS of the significant associations from the main PheWAS, covarying for PGS related to depression, schizophrenia, and suicide attempt (European ancestries only). Lastly, to adjust for unmeasured confounders we performed a within-family PheWAS of the significant associations from the main PheWAS in full-siblings identified in MVP (N = 12,127, European ancestries only). EXT PGS was associated with outcomes across all bodily systems, independent of risk for depression, schizophrenia, or suicide attempt. Within-family analyses uncovered robust associations between EXT and consequences of substance use disorders, including chronic liver disease, chronic airway obstruction, and viral hepatitis C. These results demonstrate a shared polygenic basis of EXT across populations of diverse ancestries and highlight the negative consequences of EXT for health and functioning in the US veteran population.

Dr. Harvey has served as a consultant to multiple pharmaceutical companies and device manufacturers on phase 2 or 3 development; this consulting work has been determined to be unrelated to the content of the paper. No other authors report any relevant conflicts of interest.

The Million Veteran Program (MVP) is funded by grant #MVP000 from the VA Office of Research and Development (ORD). This work was also funded by grant #1I01CX001729 from the Clinical Services Research & Development (CSRD) Service of VA ORD to Drs. Beckham and Kimbrel, by the MVP CHAMPION program, which is a collaboration between the VA and the Department of Energy (DoE), and by a CSRD Senior Research Scientist award (lK6BX003777) to Dr. Beckham. Drs. Barr, Bigdeli, Aslan, and Harvey are supported by VA Cooperative Studies Program (CSP) #572. Drs. Peterson, Bigdeli, and Meyers are supported by the National Institute of Mental Health (R01MH125938). Dr. Peterson is also supported by the National Institute on Alcohol Abuse and Alcoholism (P50AA022537) and the Brain Behavior Research Foundation NARSAD grant 28632 PS Fund. Dr. Sanchez-Roige was supported by funds from the California Tobacco-Related Disease Research Program (TRDRP; Grant Number T29KT0526 and T32IR5226) and the National Institute on Drug Abuse (DP1DA054394). Dr. Mallard is supported by funds from NIH T32HG010464. The content is solely the responsibility of the authors and does not necessarily represent the official views, policy, or position of the National Institutes of Health or the Department of Veterans Affairs (VA).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the Veterans Affairs (VA) Central Institutional Review Board, and all patients provided written informed consent.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Publicly available summary statistics are available through their respective consortia websites.