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Chunk #36 — Discussion

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Linking genes, circuits, and behavior: network connectivity as a novel endophenotype of externalizing.
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This study has several strengths including analysis of multiple levels of analysis (genes, brain circuits, and behavior), a relatively large neuroimaging-genetics sample, and use of thousands of loci to identify genetically-associated brain circuits. Several limitations should also be considered. First, we were unable to model the latent externalizing spectrum because a measure of antisocial behavior and/or trait constraint was not available, a limitation that may have impacted associations between the externalizing PS and externalizing psychopathology (i.e., alcohol and substance use disorders) in this sample. Given that the externalizing PS was developed to capture genetic risk for comorbidity among externalizing disorders, assessing the covariance among alcohol/substance use disorders and antisocial behavior may be necessary to detect a robust polygenic association with these phenotypes. Second, although our ability to detect small effects was limited by the modest sample size, the sample was comparable to other recent neuroimaging-genetic studies (Little et al., 2015; Pagliaccio et al., 2015). Further, we cannot say definitively that the current results will generalize to the latent externalizing spectrum. Third, we did not have an independent sample to examine