Despite convincing evidence that TS is a genetically inherited disorder, linkage analyses have yet to identify a definitive TS susceptibility gene. Potentially confounding factors include the complex inheritance pattern seen in many TS families; non-genetic (i.e., environmental) contributions and also the presence of noninherited or alternatively-inherited forms of TS in the population. Additionally, because a number of related conditions, including chronic motor tics and obsessive-compulsive behavior, also run in TS families, there is considerable debate over how to incorporate these family members into the genetic analyses. Our project aims to address some of these issues using a two pronged approach. First, using existing data obtained from the recently completed sib-pair screen, we will perform a family-based association study. This strategy has the ability to detect association of disease alleles in families that demonstrate bilineal transmission of the disease, a phenomenon that has been documented in many TS kindreds. This approach enables us to confirm genetic regions of interest (ROIs) identified in the sib-pair linkage analysis and to localize potential additional ROIs. Second, using the already developed clinical database we will try to identify quantitative clinical variables that may represent more homogeneous, heritable phenotypes for the genetic analysis. We will then repeat the association study using the revised phenotypes in hope of finding additional gene ROIs. Lastly, for any positive associations identified in the above studies, we will generate high-density genetic marker maps (SNP maps) and haplotypes around the ROIs with the goal of identifying TS susceptibility genes. Jeremiah M. Scharf, M.D., Ph.D. Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts Award: $39,985 Tourette Association of America Inc. – Research Grant Award 2005-2006