Psychosis risk variants and cognitive control in clinically-referred youth

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 DESCRIPTION (provided by applicant): Family, twin and prospective studies of psychosis provide strong but indirect evidence that impaired cognitive control is a manifestation of underlying genetic risk for this devastating form of psychopathology. Findings from recent, large-scale genomewide studies now offer the chance to extend this line of investigation directly to molecular genetic data. In response to PAR-14-007, we aim to capitalize on an available data set to pursue such analyses. Specifically, we will examine emerging psychosis-relevant genetic variants in relation to three constructs (working memory, inhibition and goal maintenance) that overlap with the domain of cognitive control, as defined in NIMH's Research Domain Criteria (RDoC). RDoC was developed precisely to encourage investigation of genetic advances such as these in relation to dimensional traits unconstrained by conventional diagnoses. Currently, we are near-completion of a pilot clinical research cohort of youth uniquely-suited to such investigation. In this sample, subjects are ascertained, regardless of diagnosis, as consecutive referrals for neuropsychiatric evaluations that include cognitive assessment. Using these data in this R03, we will test the hypothesis that, across diagnostic boundaries, a greater burden of common genetic variants that confer risk for psychosis associates with greater impairment in our three aspects of cognitive control. Second, we will test the hypothesis that variation in psychosis-relevant gene sets that support synaptic communication and plasticity will similarly associate with variation in these aspects of cognitive control. Based on our preliminary data, we expect that our findings will advance the core tenets of RDoC and suggest that genetic risk for psychosis operates beyond conventional diagnostic boundaries and can be detected in relation to cognitive control phenotypes measurable in youth. These data will further help to link these cognitive constructs to particular biological systems. As such, these data will allow us to refine cognitive phenotypes we investigate as we enlarge our sample (under separate funding) and work to improve pathophysiologically-based models of the unfolding of genetic risk for psychosis. Eventually, such findings could facilitate earlier and more effective interventions in youth at risk for severe neuropsychiatric illness.