Schizophrenia is a debilitating psychiatric illness that renders enormous individual, societal and public health burdens. The goal of my project is to use copy number variant (CNV) analysis as a gateway to gene discovery for schizophrenia. As my dissertation project, I propose to identify a potential disease-causing gene, by CNV analysis, then to experimentally characterize its variation in schizophrenia cases and controls. My proposed experimental approach is based on the hypothesis is that many different individually rare, deleterious mutations in many different genes contribute to the illness. Our recently published data supports this approach, and the role of rare large effect mutations in schizophrenia. My project will involve three steps. First, I will characterize rare genomic deletions and duplications (CNVs) that arise in persons with schizophrenia but not in healthy persons. I will select candidates from the genes impacted by these events, prioritizing those involved in neurodevelopmental processes and/or that have been previously implicated in neuropsychiatric illnesses. Second, I will resequence the exons and promoter regions of three promising candidate genes in unrelated persons with schizophrenia and in controls. I hypothesize that persons with schizophrenia are more likely than controls to harbor deleterious rare point mutations and frameshifts in these candidate genes. Third, based on the above results, I will select one promising candidate gene and experimentally characterize the functional impact of mutant alleles detected in cases. Identifying a gene related to schizophrenia has the potential to lead to improved diagnostic methods and treatments for individuals with the illness.
|Rippey, Caitlin; Walsh, Tom; Gulsuner, Suleyman et al. (2013) Formation of chimeric genes by copy-number variation as a mutational mechanism in schizophrenia. Am J Hum Genet 93:697-710|