Several family and twin studies have provided strong indications that genetic factors are impli- cated in the cause of Tourette Syndrome (TS). It is currently thought that the mode of inheritance is much more complex than initially appreciated, and may involve genes of major effect along with others acting as modifiers. At the same time, it has become clear that environmental factors play a role as well. Recently performed genome scans identified several chromosomal regions that may harbor susceptibility genes for TS. Among them, a region close to the end of the long arm of chromosome 17 (17q25) is of special interest. This project focuses on the investigation of 17q25 as a candidate susceptibility region for TS. More specifically, we will try to replicate previous findings and also narrow down the large candidate interval which extends over several hundreds of thousands base pairs of DNA. Although the mapping and sequencing of the entire human genome is being touted as “finished,†there is still much uncertainty about the sequence of the 17q25 region. Therefore the first step in this project will be resolving and refining the genetic map of 17q25. We will use a very dense map of DNA markers (i.e. distinct polymorphic segments of DNA) spanning the entire region of interest that will provide fine resolution. All analyses will be performed on four large multigenerational families with multiple affected members with TS. As an additional resource, information about the frequencies and the location of the markers used will be obtained by studying a large panel of individuals from around the world. Application of the refined genome characterization of TS will involve both non-parametric linkage methods and association (Transmission Test for Linkage Disequilibrium-TDT). Non-parametric linkage analysis does not require the assumption of any specific model of inheritance, but rather tests whether affected relatives inherit identical copies of a DNA marker more often than expected by chance. The TDT on the other hand simply looks at the number of parents who transmit one specific variant of a marker to their affected children and compares them with the number of parents who transmit the other variant. The parents used for the analysis must carry two different variants of the marker. Whatever the result, resolution of the possible involvement of a TS susceptibility gene in the 17q25 region could clarify the complex genetics of the disorder. Eventually the identification of the genetic factors involved will lead to a better understanding of the basic cause of the disorder providing a model for other behavioral disorders of childhood that share clinical manifestations with TS e.g. ADHD and OCD. Finding the genes responsible for TS will illuminate the biological and biochemical etiology of the disorder by examining the function of the gene products. Furthermore, it will be a step towards the disentanglement of the relative contribution of genetic and environmental factors involved and will facilitate the identification of non-genetic factors contributing to the development of TS. There will also be important implications for progress in clinical research. By stratifying individuals with TS according to known genetic factors, it will be possible to reassess diagnostic criteria, neuroimaging findings and psychopharmacology. Ultimately clarifying the relative contribution of genetic and environmental factors in the development of TS will lead to improved treatment and better management of the condition. Peristera Paschou, Ph.D., Dept. of Genetics and Child Study Center, Yale University School of Medicine, New Haven, CT Award: $40,000 In memory of J. Stephen Fink, M.D., Ph.D. and his many years of service on the Tourette Association’s Scientific Advisory Board Tourette Association of America Inc. – Research Grant Award 2003-2004
Fine Mapping of 17q25 as a Candidate Susceptibility Region for Tourette Syndrome
Grant Type
Basic
Grant Year
2003-2004
Institution Location
CT
Institution Organization Name
Yale University
Investigators Name
Paschou, Peristera, PhD