This is a proposal to identify the chromosomal location of genes responsible for Tourette Syndrome (TS), an inherited disorder characterized by motor and vocal tics. They plan studies of two genetically homogeneous populations that have expanded rapidly over the past few hundred years: that of the Central Valley of Costa Rica (CR) and that of Ashkenazi Jews in the United States. TS patients in these populations may have inherited a susceptibility to this disorder from one or a few common ancestors. TS genes will be mapped by searching for genomic regions that TS patients share identical by descent (IBD) from such ancestors; these regions will include the TS genes, and may differ between the two populations. They will search for IBD regions by randomly sampling only affected individuals and their parents from these isolated populations. The study sample will consist of individuals moderately to severely affected with TS, about 100 from CR and about 200 Ashkenazim. Diagnostic assessment will include interviews of patients and family members and review of medical records; final diagnoses will be assigned through a 'best estimate' consensus process conducted by experts in diagnosing TS. Genealogies will be obtained for all subjects, who will be included in the study only if most of their ancestors were from the target populations. The samples will be genotyped using markers distributed throughout the genome. Evaluation of IBD in each genome region will be accomplished using association tests. Their computer simulation power studies show a high probability of detecting TS loci in each study population, even if TS is etiologically heterogeneous within each population. Once TS genes are localized, fine-mapping studies will begin, leading to positional cloning efforts. Also, clinical questions relevant to understanding the cause and course of TS will be addressed using the patients sampled for the PGM studies. They have completed preliminary studies to show the feasibility of the sampling, diagnostic, and genotyping approaches described in this proposal. The sampling will be facilitated by ongoing collaborations in CR and new collaborations with several TS centers in the U.S.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS037484-04
Application #
6467353
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Finkelstein, Robert
Project Start
1998-04-30
Project End
2002-01-31
Budget Start
2000-09-01
Budget End
2001-01-31
Support Year
4
Fiscal Year
2000
Total Cost
$312,675
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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
Paschou, Peristera; Yu, Dongmei; Gerber, Gloria et al. (2014) Genetic association signal near NTN4 in Tourette syndrome. Ann Neurol 76:310-5
McGrath, Lauren M; Yu, Dongmei; Marshall, Christian et al. (2014) Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study. J Am Acad Child Adolesc Psychiatry 53:910-9
Davis, Lea K; Yu, Dongmei; Keenan, Clare L et al. (2013) Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture. PLoS Genet 9:e1003864
Chen, Kevin; Budman, Cathy L; Diego Herrera, Luis et al. (2013) Prevalence and clinical correlates of explosive outbursts in Tourette syndrome. Psychiatry Res 205:269-75
Nag, Abhishek; Bochukova, Elena G; Kremeyer, Barbara et al. (2013) CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1. PLoS One 8:e59061
Scharf, J M; Yu, D; Mathews, C A et al. (2013) Genome-wide association study of Tourette's syndrome. Mol Psychiatry 18:721-8
Reich, David; Patterson, Nick; Campbell, Desmond et al. (2012) Reconstructing Native American population history. Nature 488:370-4
Scharf, Jeremiah M; Mathews, Carol A (2010) Copy number variation in Tourette syndrome: another case of neurodevelopmental generalist genes? Neurology 74:1564-5

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