The proposal outlines the goals of an NIMH Research Scientist Award (RSA) application. The proposed award will enable the applicant to continue his research on developmental psychopathology. The long term objective of the applicant is a better understanding of the role of genetic and environmental factors in childhood neuropsychiatric disorders through the study of the specific disorders, Gilles de la Tourette's syndrome (GTS) and obsessive compulsive disorder (OCD). Recent research has led to several advances in the understanding of GTS, OCD and related conditions: 1) there is a greater range of phenotypic expression for GTS (including chronic tics and OCD); 2) GTS, OCD and related disorders are much more common than had previously been thought; and 3) the syndrome appears to be transmitted as an autosomal dominant trait. Furthermore, the prevalence of GTS, OCD and associated illnesses and their debilitating effects on those afflicted makes these conditions a major public health problem. Understanding the genetics of GTS, OCD and associated behaviors will be of direct benefit to patients concerned about recurrence in their families; ultimately, clarifying the genetics of these conditions may elucidate their pathogenesis. Data collection has been completed for 85 GTS, 100 OCD and 33 control families. Results from preliminary analyses replicate earlier findings that suggest that there is an etiologic relationship between GTS and OCD and that the mode of transmission of GTS and related disorders is consistent with autosomal dominant inheritance. The applicant is proposing to collect additional data to help characterize more completely the nature of the relationship between GTS, OCD and other traits. The OCD sample will be enlarged to include 40 families of child OCD probands. These families will allow a more direct comparison of families of young children. Since GTS is a childhood disorder, it is important to compare expression of the syndrome to the expression of OCD in children. Studying the families of childhood OCD probands should help to clarify further the transmission of both GTS and OCD and to further understanding of the familial relationship of the two disorders. In addition, data collection for genetic linkage studies of GTS and OCD will continue. These studies will be expanded to include smaller families and sib-pairs. PCR based methods for DNA typing will be employed. The linkage data will allow confirmation of findings from segregation analyses and isolation and characterization of any genetic loci. Finally, a prospective study of young unaffected children who have first degree relatives affected with GTS and/or OCD will be expanded. Thirty-three young children have already been enrolled. The families of 30 additional children at risk for GTS, 60 children at risk for OCD and 30 control children will be enrolled. This study will help to identify """"""""non-genetic"""""""" factors important for onset and variable expressions of GTS, OCD and related disorders. Data from these new family, linkage and prospective study samples will help identify specific genetic and environmental factors associated with the variable expression of GTS, OCD and related behaviors. In all cases, information will be obtained by direct structured assessment of all pertinent family members. The candidate's plans will allow continued integration of family, prospective longitudinal and linkage study methodologies. The combination of approaches should provide powerful methods for the genetic study of childhood disorders.
