Gilles de la Tourette Syndrome (GTS) is a common, highly heritable, childhood-onset neuropsychiatric disorder that is characterized by marked clinical heterogeneity and variable response to existing treatments. The purpose of this Mentored Career Development Award in Patient-Oriented Research (K23) is to train the candidate in statistical, genetic and clinical epidemiologic methods so that he can become an independent investigator in translational, clinical genetic research. The research plan consists of: 1) a clinical phenotyping aim using item-level exploratory and confirmatory factor analysis to define homogeneous, symptom-based GTS "subphenotypes" that may more adequately capture the diverse clinical features of the disease;2) a secondary analysis of a GTS genome-wide association study (GWAS) using the heritiable subphenotypes in Aim 1 to identify GTS susceptibility alleles;3) a training aim in which the candidate will participate in selected aspects of his co-mentor's pilot, randomized controlled trial of combined behavioral therapy and pharmacotherapy for GTS to acquire the skills and experience necessary to conduct future GTS clinical trials that can incorporate phenotypic and genetic predictors of treatment response. ' The proposed study will be conducted at Massachusetts General Hospital under the mentorship of David Pauls, Ph.D., an expert in GTS phenotypic and genetic research, and the co-mentorship of Sabine Wilhelm, Ph.D., an expert in GTS treatment research. A group of nationally-recognized mentors and consultants, both local and external, will provide additional mentoring in specialized areas of expertise relevant to each research and training goal. The career development plan includes a didactic component combining coursework at the Harvard School of Public Health and Harvard University Department of Psychology with guided tutorials in study design, biostatistics, statistical genetics, and clinical thals methods. This integrated research and training program will lay the groundwork for future, multi-center pharmacogenetic studies of GTS treatment response and will prepare the candidate to submit an R01 application for translational genetic studies of GTS and related disorders.

Public Health Relevance

This research aims to define more precise disease definitions for GTS, to identify GTS susceptibility genes, and to train the investigator in clinical trials methods so that he can apply these novel disease definitions and genes to future GTS treatment studies. Completion of this study will train the investigator to become a leader in translational research aimed at developing personalized treatments for GTS patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23MH085057-04
Application #
8253727
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Garriock, Holly A
Project Start
2009-08-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$185,820
Indirect Cost
$13,767
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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
Miller, Laura L; Scharf, Jeremiah M; Mathews, Carol A et al. (2014) Tourette syndrome and chronic tic disorder are associated with lower socio-economic status: findings from the Avon Longitudinal Study of Parents and Children cohort. Dev Med Child Neurol 56:157-63
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
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; Fernandez, Thomas V; Mathews, Carol A et al. (2014) The Inheritance of Tourette Disorder: A review. J Obsessive Compuls Relat Disord 3:380-385
Mathews, Carol A; Scharf, Jeremiah M; Miller, Laura L et al. (2014) Association between pre- and perinatal exposures and Tourette syndrome or chronic tic disorder in the ALSPAC cohort. Br J Psychiatry 204:40-5
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
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
O'Rourke, Julia A; Scharf, Jeremiah M; Platko, Jill et al. (2011) The familial association of tourette's disorder and ADHD: the impact of OCD symptoms. Am J Med Genet B Neuropsychiatr Genet 156B:553-60

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