The focus of this competing continuation proposal is the localization and characterization of susceptibility genes for Tourette's Disorder (TD) and related conditions. The investigators are members of a longstanding international collaboration, the Tourette Syndrome Association International Consortium on Genetics (TSAICG). Previous studies completed by members of this group suggest that the mode of transmission of TD and related disorders is consistent with the existence of genes that have a significant impact on the manifestation of TD. During the current award we conducted a genomewide linkage analysis of our samples of affected sibpair and multigenerational families. The results pointed strongly to a TD locus on Chromosome 2p [-log(p) = 4.00] and also provided evidence for several additional TD localizations, with -log(p) scores ranging from 2.0 to 3.5. We are proposing three genetic mapping studies using high-throughput SNP genotyping: Project 1 will follow up our linkage findings with fine-mapping genotyping, focusing particularly on 2p; Project 2 will search for additional TD loci through a whole genome association study on 800 trios ascertained from isolated populations; Project 3 will follow up the results of Projects 1 and 2, with a very dense set of SNPs to be genotyped in a sample (n=7200) with substantial power to detect association. The results of Project 3 will lead to genetic investigation of a small number of positional candidate genes. Functional studies of the most promising candidate genes identified through the above studies will be undertaken. Phenotypic data for new subjects sampled during the first two years of this proposal will be obtained by direct semi-structured interview of affected children and both parents. Additional analyses are proposed to define more accurately the inherited components of the TD phenotype. ? ? ?
| Khramtsova, Ekaterina A; Heldman, Raphael; Derks, Eske M et al. (2018) Sex differences in the genetic architecture of obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet : |
| Greenberg, Erica; Tung, Esther S; Gauvin, Caitlin et al. (2018) Prevalence and predictors of hair pulling disorder and excoriation disorder in Tourette syndrome. Eur Child Adolesc Psychiatry 27:569-579 |
| 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 |
| Willsey, A Jeremy; Fernandez, Thomas V; Yu, Dongmei et al. (2017) De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron 94:486-499.e9 |
| 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 |
| Hirschtritt, Matthew E; Darrow, Sabrina M; Illmann, Cornelia et al. (2016) Social disinhibition is a heritable subphenotype of tics in Tourette syndrome. Neurology 87:497-504 |
| Lek, Monkol; Karczewski, Konrad J; Minikel, Eric V et al. (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285-91 |
| Georgitsi, Marianthi; Willsey, A Jeremy; Mathews, Carol A et al. (2016) The Genetic Etiology of Tourette Syndrome: Large-Scale Collaborative Efforts on the Precipice of Discovery. Front Neurosci 10:351 |
| 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 |
Showing the most recent 10 out of 38 publications
