Using the Genetic Architecture of Externalizing Disorders to Aid in Gene Identification

Twin and family studies have unambiguously demonstrated a shared genetic architecture across disorders and traits characterized by behavioral disinhibition and impulsivity. The underlying latent factor has been called... [ view full abstract ]

Twin and family studies have unambiguously demonstrated a shared genetic architecture across disorders and traits characterized by behavioral disinhibition and impulsivity. The underlying latent factor has been called Externalizing, and is highly heritable.  Externalizing is a core feature of many psychiatric and substance use disorders, and encompasses multiple clinical diagnoses across development, including attention deficit hyperactivity disorder, conduct disorder, oppositional defiant disorder, antisocial personality disorder, alcohol use disorders, and other substance use disorders, as well as personality traits and behaviors characterized by under-control.  Capitalizing on the known genetic overlap, we have launched a new consortium that will employ genome-wide association studies (GWAS) of externalizing phenotypes, with the goal of identifying genes involved in the shared underlying liability to Externalizing versus genes unique to specific phenotypes, and  boosting statistical power for GWAS of specific externalizing phenotypes that are currently available in only relatively small samples. We apply Genomic SEM, a new multivariate method, which applies structural equation modeling to summary statistics from genetically correlated traits. With the method we perform exploratory and confirmatory factor analyses, allowing for sample overlap. Our initial analyses include GWAS summary statistics for addictive behaviors (n ~ 157,000), ADHD (n ~ 53,000), alcohol consumption (n ~ 414,000), antisocial behavior (n ~ 16,000), childhood aggression (n ~ 19,000), lifetime cannabis use (n ~ 32,000), and several risk behaviors (n ~ 370,000 – 405,000). We present results from the initial analyses of these phenotypes and our planned future directions. We conclude with details about the Externalizing Consortium, in order to invite groups to participate in the next wave of analyses.