Project 443508

Psychiatric disorders are major health problem that can severely impact affected individuals' quality of life. The majority of associated DNA variants found through genetic studies of psychiatric disorders are expected to change the expression of the risk genes. Gene expression is regulated by multiple mechanisms including alternative splicing. Splicing is the process by which different parts of the gene are linked together to create a functional protein and alterations in this process allow diversity in the proteins that can be expressed from a single gene in different tissues. Deregulation of this tightly controlled process however can result in disease. We mined large datasets of DNA variants predicted to alter, or are correlated with, gene splicing changes and identified those that were also associated with psychiatric disorders. Using those datasets we identified candidates, and confirmed alternatively spliced genes for 6 of the 13 tested thus far, 4 of which were correlated with genetic risk. Three of these are involved in mitochondrial function (APOPT1, AS3MT, NEK4), implicated in psychiatric disorder by multiple lines of evidence. Cytochrome c oxidase (COX) deficiency is associated with bipolar disorder, and deleterious changes in APOPT1 results in a COX deficiency. Our pilot data thus links genetic risk variants altering splicing to a testable cellular phenotype associated with disease. Based on our data, we propose to use this approach to study the remaining genes identified from our informatics approach as well as to identify new candidates as genetic studies for additional disorders arise. We will further use molecular assays that allow us to identify which of the DNA variants change splicing, followed by functional studies in human neural cells. The foundational knowledge provided by our study will offer the possibility of developing new therapies targeted to the risk genes or their protein products.