This proposed research leverages a large clinical and genetic dataset of individuals and families with Tourette Syndrome (TS) to identify heritable symptom-based phenotypes and conduct quantitative genome-wide association studies (qGWAS) with the ultimate goal of identifying genetic variants that contribute to TS susceptibility. TS is a complex developmental neuropsychiatric disorder that affects 1/150 to 1/300 children world-wide. Although the core features of TS (the presence of motor and vocal tics) are fairly straightforward, TS is phenotypically diverse, with some individuals manifesting only mild tics with little to no functional impact and others manifesting moderate to severe tics with marked impairment. Individuals at all levels of tic severity and in all age groups may also experience a range of co-occurring conditions that lead to significant functional impairment, most commonly obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD), but also including other mood, anxiety, and disruptive behavior disorders. This phenotypic heterogeneity has complicated etiological and treatment studies of TS, as well as impacting clinical care. This study will use novel analytic approaches such as factor mixture modeling to 1) examine the frequencies, patterns, and correlates of co-occurring psychiatric disorders, 2) identify TS phenotypic subtypes based on patterns of tic and related symptoms and co-occurring conditions (including autism spectrum symptoms), 3) examine the heritabilites and transmission patterns of these subphenotypes, and 4) conduct quantitative genome-wide association studies with the most heritable of the identified subphenotypes. We have extensive clinical data (lifetime and current symptomatology) on over 2,100 TS-affected individuals and 2,500 of their biological first-degree relatives, as well as genome-wide genetic data on 1006 of the TS cases, providing an unparalleled opportunity to further our understanding of the presentation TS. The work proposed in this application has relevance both clinically, as we will be able to determine rates and patterns of co-occurring disorders, which, as mentioned, are responsible for the majority of the impairment in TS, and scientifically, as it provides additional avenues for genetic and other investigations into the etiology and pathophysiology of TS and other related neurodevelopmental disorders.

Public Health Relevance

Tourette Syndrome (TS), which affects 1/150 to 1/300 children world-wide, is defined by neurological symptoms (the presence of motor and vocal tics). However, >90% of individuals with TS also have co- occurring psychiatric disorders, and it is these disorders that are responsible for the majority of the impairment. In addition, although highly heritable, no definitive susceptibility genes have yet been identified for TS. This proposal uses a unique database of >4000 TS-affected individuals and their relatives to examine tic symptom patterns and rates and impact of co-occurring disorders within individuals and families and to conduct genetic studies using the identified patterns. The ultimate goal to identify additional TS susceptibility genes is a crucial step in better understanding the causes of TS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH096767-03
Application #
8763948
Study Section
Child Psychopathology and Developmental Disabilities Study Section (CPDD)
Program Officer
Friedman-Hill, Stacia
Project Start
2013-01-23
Project End
2015-07-31
Budget Start
2014-12-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Psychiatry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
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
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
Zilhão, N R; Olthof, M C; Smit, D J A et al. (2017) Heritability of tic disorders: a twin-family study. Psychol Med 47:1085-1096
Huisman-van Dijk, Hilde M; Schoot, Rens van de; Rijkeboer, Marleen M et al. (2016) The relationship between tics, OC, ADHD and autism symptoms: A cross- disorder symptom analysis in Gilles de la Tourette syndrome patients and family-members. Psychiatry Res 237:138-46
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
Darrow, Sabrina M; Verhoeven, Josine E; Révész, Dóra et al. (2016) The Association Between Psychiatric Disorders and Telomere Length: A Meta-Analysis Involving 14,827 Persons. Psychosom Med 78:776-87
Scharf, Jeremiah M (2016) Parity in Tourette Syndrome: Reproducible Risk Factors for an Underrecognized Neurodevelopmental Disorder. J Pediatr 171:17-9
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

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