Our efforts to map one or more Tourette Syndrome genes to specific chromosomal sites through demonstration of coinheritance (linkage) to DNA polymorphisms are continuing. DNA samples from several large Tourette kindreds, including one from Wisconsin, have been obtained. About 120 highly informative microsatellite DNA polymorphisms have been tested to date at Marshfield, and over 500 markers total have been tested by members of the Tourette genetics consortium. No strong evidence for linkage has yet been found, although suggestive results have been observed, especially for markers located on the long arm of chromosome 3. In the coming grant year, we will attempt to confirm the suggestive results through the testing of additional markers in these chromosomal regions and through the testing of additional families. Greatly improved linkage map positions for the microsatellites will also be helpful in filling gaps in the coverage of each of the chromosomes. Peter Heutink, a graduate student in Dr. Ben Oostra’s laboratory at Erasmus University in The Netherlands, visited Marshfield for a period of about two months to carry out genotyping of Dutch Tourette families using the microsatellites. Alternative methods of analysis of genotyping data such as sib-pair analysis were employed. Such methods have the advantage of being independent of specific models of inheritance. Although the heritable nature of Tourette Syndrome is firmly established, gene mapping is complicated by incomplete penetrance and variable expression of Tourette genes, by the possibility of two or more distinct Tourette genes located at different chromosomal sites (locus heterogeneity), and by the difficulty of diagnosing family members with subtle tics or obsessive-compulsive behaviors. However, continued accumulation of genotyping data and more refined analysis of these data currently offer the most promising approach for understanding the molecular genetics of this disorder. James L. Weber, Ph.D., Patricia Wilkie, Ph.D., Peter A. Ahmann, M.D. Marshfield Medical Research Fdn., Marshfield, WI Award $25,000 Tourette Association of America Inc. – Research Grant Award 1991