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

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.