Schizophrenia genetics, neural and cognitive phenotypes, and social functioning

DESCRIPTION (provided by applicant): Deficits in social functioning are consistently linked with schizophrenia and schizophrenia risk. Research has uncovered specific neural and cognitive mechanisms that contribute to social functioning in healthy individuals, and abnormalities in some of these mechanisms have been identified in both schizophrenia patients and their unaffected first-degree relatives [1-3]. This suggests that genetic risk for schizophreni may manifest in terms of variations in these basic neural and cognitive mechanisms, even in individuals without a mental disorder. Recent genetic discovery efforts have begun to unravel the genetic architecture of schizophrenia, yielding (1) methods for estimating schizophrenia polygenic risk, or the aggregate risk arising from variations in single-nucleotide polymorphisms across the entire genome [4], and (2) specific genetic variants that are associated with schizophrenia, even after genome-wide statistical correction [5]. With these new discoveries, there are new opportunities for identifying potential pathways leading from genetic risk to deficit in neural function, information processing, and behavior that ultimately may lead to schizophrenia. Here, I focus on the relationship between recently identified genetic predictors and intermediate neural and cognitive phenotypes related to social functioning. The current proposal aims to answer the following questions: (1) How much of the variation in intermediate neural/cognitive phenotypes related to social functioning can be explained by variations in single-nucleotide polymorphisms? (2) Does estimated polygenic risk for schizophrenia predict variations in social functioning phenotypes? (3) Do recently identified schizophrenia genetic risk variants predict variations in social functioning phenotypes? The proposed research uses intermediate phenotypes as a way of gaining traction on the mechanisms that lead from validated genetic risk factors to mental disorders. The proposed research may enable the identification of pathways through which genetic risk factors influence risk for developing schizophrenia, through their action on particular aspects of neural architecture and social cognition. Identification of these specific pathways will suggest new hypotheses for the pathogenesis of schizophrenia and offer potential targets for treatment, intervention, and further research.