Tourette Disorder (TD) is a developmental neuropsychiatric syndrome characterized by the combination of persistent vocal and motor tics. While initially considered rare, the world-wide prevalence is now estimated to be 0.3-1%. Both as a consequence of potentially disabling symptoms as well as very high rates of psychiatric co-morbidity, particularly with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD), TD represents a significant public health concern. Despite decades of evidence supporting a significant genetic contribution, progress in identifying risk alleles has been slow. This difficulty is thought to be, in part, a consequence of complex inheritance and substantial genetic and phenotypic heterogeneity. This collaborative study unites an international group of highly expert clinicians specializing in TD with statistical and molecular geneticists and is motivated by three central hypotheses: 1) that a key rate- limiting factor for TD gene discovery has been the paucity of publically available, large-scale biomaterial resources of the kind that are now commonplace for many neuropsychiatric disorders;2) based on recent data from a host of other genetically complex disorders, a comprehensive genomics study of TD will require large samples sizes and should focus on the potential contribution of rare as well as common alleles and both sequence and structural variants;and 3) an increased understanding of the genetic etiology of TD will translate into novel and more effective approaches to treating this often-debilitating disorder, and consequently will have marked public health benefits. The application elaborates three specific aims:
Specific Aim 1 : To recruit 5050 individuals with TD (and their family members), and make DNA, cell-lines, cDNA/RNA and phenotypic data publicly available within one year of collection. The sample will include a subset of 3195 European Caucasian (EC) probands;1250 Korean probands, and 3295 parent-child trios allowing for the study of de novo variation. We will also recruit each year at least 10 TD pedigrees with 4 or more affected members as a resource for family-based gene discovery.
Specific Aim 2 : To employ state-of-the-art techniques to identify and confirm rare and common variants contributing to TD. We will genotype the sample on Illumina HumanOmni2.5 -Quad BeadChips to support copy number variation (CNV) analysis (Aim 2A) and genome wide association studies (GWAS) (Aim 2B);whole exome sequencing will be employed in select, multiply-affected TD pedigrees (Aim 2C);and we will follow up on the most promising loci identified in the aforementioned studies using a pooled next generation re-sequencing strategy (Aim 2D) at two time points, evaluating a minimum of 50 genes in a total of 3195 EC and 3195 matched controls;
Specific Aim 3 : To perform preliminary analyses of 300 transcriptomes of TD subjects to investigate the implications of selected structural and sequence variations for cis, trans and genome-wide expression. With no cost to this project, PAXgene tubes will be collected from all subjects and made available to the scientific community to enable future studies by our group and others.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH092293-02
Application #
8333310
Study Section
Special Emphasis Panel (ZRG1-PSE-H (60))
Program Officer
Addington, Anjene M
Project Start
2011-09-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$121,316
Indirect Cost
$8,323
Name
Rutgers University
Department
Genetics
Type
Schools of Arts and Sciences
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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
Moya, Pablo R; Wendland, Jens R; Rubenstein, Liza M et al. (2013) Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette's disorder. Mov Disord 28:1263-70
Moya, Pablo R; Dodman, Nicholas H; Timpano, Kiara R et al. (2013) Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes. Eur J Hum Genet 21:850-4
Scharf, J M; Yu, D; Mathews, C A et al. (2013) Genome-wide association study of Tourette's syndrome. Mol Psychiatry 18:721-8
Fernandez, Thomas V; Sanders, Stephan J; Yurkiewicz, Ilana R et al. (2012) Rare copy number variants in tourette syndrome disrupt genes in histaminergic pathways and overlap with autism. Biol Psychiatry 71:392-402