Psychiatry and the Behavioral Sciences
Zilkha Neurogenetic Institute
- Genetics of neuropsychiatric disorders, including autism and schizophrenia
- Epigenetic mechanisms of neuropsychiatric disorder risk
- Cellular functions of genetic and epigenetic variants that contribute to neuropsychiatric disorders
- Co-occurring medical conditions in autism
- Pharmacogenetics - using genetic information to predict most effective treatment strategies
Research OverviewMy laboratory focuses on defining functional genetic variants that contribute to the etiology and treatment effectiveness of autism and schizophrenia. The long-term goals of these studies are to better understand the causes of the disorders and to improve the ability to treat them on an individualized basis. Genetic analyses are critical for determining the genes that contribute to autism and schizophrenia. However, the identification of disorder-associated genes is only the first step in determining the mechanisms by which dysfunction of the encoded proteins contributes to disorder etiology and, eventually, developing biologically-sound treatment options. My laboratory will integrate the results of unbiased whole-genome approaches with an understanding of neurobiological mechanisms to develop hypothesis-driven candidate gene approaches to improve the treatment of neurodevelopmental disorders.
Treatment options for schizophrenia include a number of different antipsychotic medications, each of which can be effective in a subset of patients. Based on gene expression arrays, genetic association analyses, and functional studies, it was determined that the gene encoding Regulator of G-protein Signaling 4 (RGS4) contributes to schizophrenia risk. Because RGS4 regulates activity of the same receptors that are targeted by antipsychotic medications, we hypothesized that variants of the RGS4 gene may also predict which antipsychotic drugs would be most effective for individual patients. We showed that RGS4 genotype does predict the effectiveness of antipsychotic medications. Continuing work in my laboratory seeks to determine how these genetic variants influence RGS4 expression in the brain and what other gene variants may also contribute to prediction of antipsychotic medication effectiveness in individual patients.
Autism is a complex neurodevelopmental disorder that often presents with co-occurring gastrointestinal or immune dysfunctions. We have taken the approach that there are several different types of autism, and that the genetic contributions to autism risk may be more obvious after stratifying groups with these co-occurring conditions. We showed that a functional variant of the gene encoding the MET receptor tyrosine kinase is strongly associated with autism in a subset of patients who also have gastrointestinal conditions. Because the MET receptor tyrosine kinase is a key regulator of immune responsiveness, which may influence both brain development and gastrointestinal function, my laboratory is now interested in how MET protein dysregulation in the immune system may contribute to autism risk in a subset of patients. Together with collaborators, my laboratory has generated data indicating that the functional variant in the MET gene is associated with an immune biomarker of autism risk. We are now pursuing studies that will help to define the role of the MET receptor in immune function, and how a deficit in MET expression in the immune system may contribute to autism risk. The goal of these studies is to find, for at least a subset of patients, effective treatment options for autism.