Research Overview
Identifying the genetic basis of complex neuropsychiatric phenotypes requires a multifaceted approach, including the use of increasingly sophisticated gene expression technologies. We are applying these methodologies to study schizophrenia, autism and other neurological disorder. For instance, recent expression studies suggest that abnormalities of RNA splicing and processing may contribute to the pathology of schizophrenia and Alzheimer's disease. As spatially and temporally regulated alternative splicing is considered the most important mechanism for increasing the functional diversity of proteins, it is not surprising that subtle perturbations of this process might play a prominent role in diseases of the central nervous system. Therefore, we are using a custom alternative splicing microarray to detect abnormal splice forms in schizophrenic brain. Abnormal splicing and processing of widely expressed molecules such as the glutamate type 1 transporter may also be involved in neurodegenerative disease and this is another area of investigation in the laboratory. In addition, we are also exploring potential functional relationships between RNA splicing and processing proteins with the goal of identifying candidate schizophrenia susceptibility genes.
We also have a population genetic study of autism ongoing in the Central Valley of Costa Rica. The population of the CVCR began with only a few founding families and grew exponentially in isolation until the 1970's. This type of genetically isolated founder population may be useful for mapping complex genetic traits. Although autism is a highly heritable disorder, it now appears that microduplications and deletions may explain a significant fraction of cases. It is also possible that cytogenetic abnormalities interact with autism susceptibility alleles in other genes. Array-based Comparative Genomic Hybridization, or aCGH, is a novel technology for high-throughput detection of both known and novel cytogenetic abnormalities. We are screening our autism cases using this technology in order to identify known and novel cytogenetic abnormalities associated with autism and to identify possible genotype-phenotype correlations which may help us find underlying autism susceptibility genes. For instance, we recently identified a novel atypical deletion of the Williams Beuren Syndrome deletion interval that implicates several genes likely involved in language development and socialization.
Our lab is also part of the Seaver Center for Excellence in Autism Research and we are interested in exploring the etiology of autism and response to treatment using gene expression profiling in whole blood. Identification of a gene expression profile characteristic of autism in whole blood might aid in further understanding the biology of this genetically and environmentally heterogeneous disorder. Such profiles may also provide predictors of treatment response to various pharmacological interventions including agents such as oxytocin and valproic acid. Oxytocin is a particularly promising therapy for autism and to understand its efficacy in disease we must also understand its effects in healthy individuals. Therefore we will be performing gene expression profiling in healthy individuals in collaboration with other investigators in the Seaver Center for Autism Research.