The aim of this Project is to gain a better understanding of the normal genetic variation at and around several genes involved in the development and function of the dopaminergic projections within the central nervous system. Several lines of evidence point to the involvement of the dopaminergic system in the etiology and pathobiology of Tourette's syndrome (TS). The genes to be studied initially are the DRD2 (dopamine receptor type D2), DRD4 (dopamine receptor type D4), and SLC6A3 (dopamine transporter) loci. Other loci involved in the dopaminergic system may be added as these studies and published research dictate. Polymorphic markers bracketing and internal to a gene will be identified. These markers will be used to examine the genetic history of a locus within at least 30 different populations through haplotype analyses. The individual polymorphisms and the haplotypes generated from these polymorphisms will be used to test for linkage disequilibrium between the marker and TS, and also to look for an association between the marker and the etiology or symptomatology of TS within our families. Haplotype analysis more finely partitions the chromosomes in the population (or family), making it more likely that one will be more strongly associated with a susceptibility variant, should one exist. An understanding of the normal allele frequency variation of a polymorphism among populations is essential for the design and interpretation of studies exploring the relevance of the polymorphism to TS and other complex disorders. There is a close interface with investigators searching for the TS vulnerability genes in a Project. As vulnerability genes are identified, a concerted effort will be made to characterize the variation at and around these loci. Knowledge generated in this project is also likely to be relevant to the other component projects in the program project. Specifically, knowledge concerning dopaminergic loci is likely to be useful in interpreting the treatment response data obtained in another Project.