Molecular Genetics of Schizophrenia Susceptibility
A main focus of our laboratory is on the genetics of schizophrenia. In collaboration with Dr. Anne Bassett, at the University of Toronto, we have conducted multiple studies on a sample of moderately large, extended families from eastern Canada. We initially identified a strong linkage peak on chromosome 1q21-22 in these families (Brzustowicz et al, Science, 2000), subsequently narrowing the linkage peak and identifying significant evidence of linkage disequilibrium to markers within the gene NOS1AP (Brzustowicz et al, American Journal of Human Genetics, 2004). We have also demonstrated altered expression of NOS1AP in post mortem brain samples of individuals with schizophrenia and bipolar disorder (Xu et al, PLoS Medicine, 2005) and have identified a specific functional polymorphism within NOS1AP that can alter gene expression (Wratten et al, American Journal of Psychiatry, 2009). Further work on the genetics and function of NOS1AP and interacting genes is ongoing.
microRNA Dysregulation in Schizophrenia and Bipolar Disorder
microRNAs are powerful regulatory molecules that are abundantly expressed in the developing and adult mammalian brain. Many primate-specific miRNAs are now known, making this class of genes attractive candidates for involvement in disorders of brain function, including schizophrenia and bipolar affective disorder. Little is known about the pattern of expression of these genes in the brains of normally developing humans or individuals with major psychiatric disorders. A variety of possible mechanisms exist through which miRNAs could be altered in disease and play a role in pathogenesis. For this project we are quantifying miRNA expression in post-mortem brain samples from individuals with schizophrenia, bipolar disorder, and psychiatrically normal controls. We are also examining changes in miRNA expression in the human brain during early development. Our colleagues Dr. Jim Milloning and Dr. Manny Dicicco-Bloom at UMDNJ-RWJMS are further characterizing the cell biology of miRNAs of interest in schizophrenia.
Schizophrenia Risk in 22q Deletion Syndrome
22q Deletion Syndrome (22qDS; also known as velocardiofacial syndrome) is a deletion syndrome of chromosome 22q11.2 characterized by cleft palate, cardiac anomalies, mild dysmorphic features, hypernasal speech, and learning disabilities. The extent of the deletion is somewhat variable, with most individuals deleted for a common 3 Mb region. The commonly deleted region includes the gene DGCR8, important in the biogenesis of microRNAs. Approximately 25% of adults with 22qDS have schizophrenia. In collaboration with Dr. Anne Bassett, at the University of Toronto, we are analyzing DNA from individuals with 22qDS with and without schizophrenia to determine changes that increase risk of psychotic illness. We are exploring how alterations in the microRNA system interact with other genetic polymorphisms to increase risk of schizophrenia in individuals with 22qDS.
Combined NIMH Studies Project (CNSP)
The goal of the CNSP project is to conduct a joint analysis of existing clinical and genetic data from multiple family and case-control studies of schizophrenia and bipolar disorder that are maintained within the NIMH Center for Genetic Studies. The CNSP project is a collaborative effort between our laboratory and the laboratory of Dr. Veronica Vieland at the Battelle Center for Mathematical Medicine in The Research Institute at Nationwide Children's Hospital & The Ohio State University. Our laboratory is conducting a review of all the phenotypic data that will be used for these analyses.