This is an application for competitive renewal of a grant aimed at identifying the genetic basis of Tourette syndrome (TS). The project is based on a genomewide population genetic mapping approach, that is, using densely spaced, highly polymorphic short tandem repeat (STR) markers to identify regions of linkage disequilibrium (LD) with TS. The LD mapping study is focused on independently ascertained TS patients (and their parents) from the isolated population of the Central Valley of Costa Rica (CVCR). The PI and collaborators have been refining approaches for analyzing such LD data. During the previous award, we sampled probands and their parents from the CVCR and initiated a genomewide LD-screen. Preliminary analyses of genotype data suggest several possible localizations for TS susceptibility genes. In particular, strong LD with the TS phenotype was observed on chromosome 17q25, a region in which linkage to TS had previously been suggested by other groups. In the renewal of this grant, sample collection, genotyping and genome-wide LD mapping will be completed for the CVCR samples. Regions highlighted from the whole genome screen will be followed up in additional TS samples from the same population. Positive findings in the follow-up studies will be used as a guide to select genome regions for fine-mapping studies. These fine scale genotyping studies of the CVCR samples and samples from collaborators, using STRs and single nucleotide polymorphisms (SNPs), will be carried out to pinpoint the location of TS susceptibility genes. In the most promising of these regions we will screen candidate genes using existing SNPs as well as using SNPs that we will identify in the study samples. By the completion of the award, we aim to identify one or more sequence variants associated with TS susceptibility.
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| 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 |
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| 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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