The long term objective of this project is a better understanding of the role of genetic and environmental factors in human neuropsychiatric disorders through the study of the specific disorder, Gilles de la Tourette's syndrome (TS) and obsessive compulsive disorder (0CD). Recent research has led to several notable advances in our understanding of TS, 0CD and related conditions: 1) there is a greater range of phenotypic expression for TS (including chronic tics and 0CD); 2) TS, 0CD 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 TS, 0CD and associated illnesses and their debilitating effects on those afflicted makes these conditions a major public health problem. Understanding the genetics of TS, 0CD 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. Date collection has been completed for 86 TS, 107 0CD and 15 control families. Results from preliminary analyses replicated our earlier findings which suggest that there is an etiologic relationship between TS and 0CD and that the mode of transmission of TS and related disorders is consistent with autosomal dominant inheritance. In this application, we are proposing to increase the number of families being studied to examine several specific hypotheses. Additional data will make it possible to characterize more completely the nature of the relationship between TS, 0CD and other traits. We will expand our sample to include 40 families of child 0CD probands. These families will allow a more direct comparison of families of young children. Since TS is a childhood disorder, it is important to compare expression of the syndrome to the expression of 0CD in children. Studying the families of childhood 0CD probands should help to clarify further the transmission of both TS and 0CD and to further our understanding of the familial relationship of the two disorders. In addition, data collection for a genetic linkage study of TS will continue and we plan to expand such a study for 0CD. In the TS families we will follow up all relatives in the study to update diagnostic information. For the 0CD study, we will obtain blood samples from all living relatives so that the DNA from the lymphocytes can be typed for restriction fragment length polymorphisms. The linkage data will allow us to confirm our findings from segregation analyses and to isolate and characterize any genetic locus. Finally, we plan to expand a prospective study of young unaffected children who have first degree relatives affected with TS and/or 0CD. Thirty young children have already been enrolled in the study. We plan to enroll the families of 30 additional children at risk for TS, 60 children at risk for 0CD and 30 control children. This study will help to identify 'non-genetic' factors important for onset and variable expressions of TS, 0CD and related disorders. Data from these new family, linkage and prospective study samples will help identity specific genetic and environmental factors associated with the variable expression of TS, 0CD and related behaviors. In all cases, information will be obtained by direct structured assessment of all pertinent family members.
| Abdulkadir, Mohamed; Mathews, Carol A; Scharf, Jeremiah M et al. (2018) Polygenic Risk Scores Derived From a Tourette Syndrome Genome-wide Association Study Predict Presence of Tics in the Avon Longitudinal Study of Parents and Children Cohort. Biol Psychiatry : |
| Darrow, Sabrina M; Grados, Marco; Sandor, Paul et al. (2017) Autism Spectrum Symptoms in a Tourette's Disorder Sample. J Am Acad Child Adolesc Psychiatry 56:610-617.e1 |
| Huang, Alden Y; Yu, Dongmei; Davis, Lea K et al. (2017) Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome. Neuron 94:1101-1111.e7 |
| Darrow, Sabrina M; Hirschtritt, Matthew E; Davis, Lea K et al. (2017) Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome. Am J Psychiatry 174:387-396 |
| Darrow, Sabrina M; Illmann, Cornelia; Gauvin, Caitlin et al. (2015) Web-based phenotyping for Tourette Syndrome: Reliability of common co-morbid diagnoses. Psychiatry Res 228:816-25 |
| Yu, Dongmei; Mathews, Carol A; Scharf, Jeremiah M et al. (2015) Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD. Am J Psychiatry 172:82-93 |
| de Leeuw, Christiaan; Goudriaan, Andrea; Smit, August B et al. (2015) Involvement of astrocyte metabolic coupling in Tourette syndrome pathogenesis. Eur J Hum Genet 23:1519-22 |
| Pauls, David L; Fernandez, Thomas V; Mathews, Carol A et al. (2014) The Inheritance of Tourette Disorder: A review. J Obsessive Compuls Relat Disord 3:380-385 |
| Paschou, Peristera; Yu, Dongmei; Gerber, Gloria et al. (2014) Genetic association signal near NTN4 in Tourette syndrome. Ann Neurol 76:310-5 |
| Pauls, David L; Abramovitch, Amitai; Rauch, Scott L et al. (2014) Obsessive-compulsive disorder: an integrative genetic and neurobiological perspective. Nat Rev Neurosci 15:410-24 |
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