Data from family-based, candidate gene, and genome-wide association studies converge to suggest a significant overlap in the molecular genetic risk factors for schizophrenia (SZ) and bipolar disorder (BD). This suggests that overlapping genetic variants that influence risk for these illnesses do so via effects on shared dimensional phenotypes. Among these shared traits, neurocognitive impairment, is of particular clinical relevance as it does not adequately respond to available treatments and it is among the strongest predictors of functional disability across both disorders. Moreover, there is strong evidence that neurocognitive impairment is influenced by genetic factors in both SZ and BD, making this an endophenotype which is critical toward understanding trans-disorder pathophysiology. The identification of the relevant molecular networks associated with neurocognitive functioning in psychosis is not only an important step in elucidating the causes of these disorders, but also in identifying novel treatment options for this disabling symptom domain. We will focus on neurocognition as a critical dimension that is directly associated with disease risk and attempt to identify the clinical and molecular factors that underlie cognitive impairment in psychosis. To do so, we will characterize a prospective sample of 300 patients with psychosis, including both affective and non-affective psychosis, and empirically classify subjects based on neurocognitive performance profiles. We will also collect blood samples for DNA extraction and genotype a targeted list of high priority SNPs (based on prior association with BD/SZ risk and/or neurocognitive functioning) using a customized array. These data will be applied to a multidimensional modeling analyses in an effort to identify the risk alleles and molecular pathways that contribute to neurocognitive impairment in psychosis.
Converging evidence suggests that patients with psychosis have persistent neurocognitive impairment, despite remission of acute affective/psychotic symptoms that contribute directly to functional disability in social, occupational, and residential status. The current study aims to identify the clinical and molecular predictors of cognitive dysfunction in patients with psychosis by incorporating comprehensive clinical and neurocognitive phenotyping and a novel genomic approach capturing common variation across the genome as well as rare structural variation. Ultimately, data derived from this project could serve to 1) elucidate underlying molecular mechanisms of overlap between bipolar disorder and schizophrenia and 2) guide future efforts toward developing novel and effective treatments for these disabling symptoms.
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