Bipolar disease (manic-depressive illness, BD) is a common mental disorder with a lifetime prevalence rate of 1%, and is one of the ten major causes of disability worldwide. Epidemiologic data implies that multiple genes and environmental factors play interacting roles in the development of bipolar. Neurogenesis and plasticity are implicated in bipolar disease. But most of the genes in the neurogenesis and plasticity system were not tested for association with BD so far. I propose to perform a systematic association test and resequencing on 35 candidate genes in this system, using -600 Single Nucleotide Polymorphisms (SNPs) in 1540 case-control bipolar samples, to determine if individual gene or multiple genes in the system confer susceptibility to BD.
The combination of very dense genotyping, re-sequencing, and statistical and genomic analyses in this cohort affords an outstanding opportunity to test the neurogenesis and plasticity hypothesis in BD, and to identify gene variants that contribute to BO susceptibility. It is our expectation that we will identify one or several valid associations with candidate genes. An understanding of the role of the associated genes and their pathways in BD susceptibility would reasonably be expected to lead to biologically-based diagnostic categories, improved prediction of susceptibility, and new molecular treatment targets.
Meanwhile, since neurogenesis and plasticity are also hypothesized in other neuropsychiatric illnesses, such as Schizophrenia, Alzheimer’s disease, and others, another important benefit of this work would be the application to those diseases. Informatics development, novel common SNPs and other variants discovered in the resequencing part of this proposal, and fine LD maps around the candidate genes derived from this project, will also be valuable for association studies in many other diseases.