Investigating the genetic basis of schizophrenia and associated cognitive deficits (360G-Wellcome-211499_Z_18_Z)

Schizophrenia desperately needs new drugs. It affects 1% of adults, is a global health problem yet medications are only partially effective. They reduce psychotic symptoms but not negative symptoms and cognitive deficits, which are key factors for explaining illness-related disability. Schizophrenia and cognition are complex but highly heritable so genetics represents a vital tool for understanding neurobiology in the absence of biomarkers. A network of 150 coexpressed genes has been identified that is conserved throughout the human cortex. It is enriched for rare and common genetic variants associated with cognitive phenotypes and neuropsychiatric disorders. I plan to use the newest/largest available genetic studies of schizophrenia and cognition ( > 380,000 individuals) to study this gene network in these phenotypes. I will use gene-set analysis to test the network for enrichment of genes associated with schizophrenia or cognition. I will quantify the proportion of SNP-based heritability for schizophrenia or cognition that can be attributed to genes in this network. I will investigate what individual genes are associated with either phenotype or with both, i.e. genes that are having a pleiotropic effect. This can point to the biological processes that underlie cognitive deficits in schizophrenia and be a foundation for new methods of treatment.