Review article
The genetics of Tourette syndrome: A review

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Abstract

Objectives

This article summarizes and evaluates recent advances in the genetics of Gilles de la Tourette syndrome (GTS).

Methods

This is a review of recent literature focusing on (1) the genetic etiology of GTS; (2) common genetic components of GTS, attention deficit hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD); (3) recent linkage studies of GTS; (4) chromosomal translocations in GTS; and (5) candidate gene studies.

Results

Family, twin, and segregation studies provide strong evidence for the genetic nature of GTS. GTS is a heterogeneous disorder with complex inheritance patterns and phenotypic manifestations. Family studies of GTS and OCD indicate that an early-onset form of OCD is likely to share common genetic factors with GTS. While there apparently is an etiological relationship between GTS and ADHD, it appears that the common form of ADHD does not share genetic factors with GTS. The largest genome wide linkage study to date observed evidence for linkage on chromosome 2p23.2 (P=3.8×10−5). No causative candidate genes have been identified, and recent studies suggest that the newly identified candidate gene SLITRK1 is not a significant risk gene for the majority of individuals with GTS.

Conclusion

The genetics of GTS are complex and not well understood. The Genome Wide Association Study (GWAS) design can hopefully overcome the limitations of linkage and candidate gene studies. However, large-scale collaborations are needed to provide enough power to utilize the GWAS design for discovery of causative mutations. Knowledge of susceptibility mutations and biological pathways involved should eventually lead to new treatment paradigms for GTS.

Introduction

In the original description of the syndrome that bears his name, Georges Gilles de la Tourette observed that the disorder was familial [1]. Subsequently, there has been considerable research devoted to systematically examining whether that original observation could be replicated and whether the observed familiality is due in part to genetic factors. These studies have included family studies, twin studies, genetic linkage studies, and genetic association (candidate gene) studies. This review is based on the comprehensive literature search of PubMed database with keywords such as Gilles de la Tourette, Tourette Syndrome, Tourette Disorder, GTS, ADHD, and OCD.

Section snippets

Family studies

Family studies have repeatedly demonstrated that Gilles de la Tourette syndrome (GTS) is highly familial. Establishing that there is familial aggregation does not “prove” that the disorder is influenced only by genetic factors, since family members also share common environmental factors. Nevertheless, results from these studies provide an important first step for determining whether genetic factors are important in the manifestation of the condition. Since first-degree relatives share on

Twin studies

Twin studies provide strong evidence for the genetic nature of GTS. The largest study included 30 monozygotic and 13 dizygotic pairs of twins [53]. These investigators utilized phone-based assessment and found that 77% of monozygotic twins were concordant for tic disorders (CT or GTS), but only 23% of dizygotic twins were concordant for these disorders [53]. Furthermore, the concordance rate of monozygotic twins reached 100% for GTS or CT when direct observational interviews were conducted [47]

Linkage analyses

Five genome wide linkage analyses have been performed to date [55], [56], [57], [58], [59]. The Tourette Syndrome Association International Consortium for Genetics (TSAICG) has conducted the largest of these genetic linkage studies. Their sample represents a joint analysis of most of the individuals contained in the four previous studies and consists of 238 nuclear families and 18 large multigenerational families totaling 2040 individuals [59]. Both parametric and nonparametric analyses were

Chromosomal translocations

Another valuable approach for identifying disease genes is the identification of chromosomal aberrations in patients. Translocations, duplications, or deletions of large chromosome segments can be visualized by karyotyping or fluorescence in situ hybridization. Newer methods for detection of duplications or deletions ranging from ∼1 kb to several megabases (Mb) in size, referred to as copy number variations (CNVs), have identified de novo and inherited CNVs associated with risk of many

Candidate gene studies

Candidate gene studies have focused mainly on genes involved in the dopaminergic pathway due to the fact that dopamine antagonists are the most effective medications for tic suppression. As shown in Table 1, similar to findings in other complex disorders [134], candidate gene association studies in GTS have not yielded any clearly replicated results that unequivocally identify a causative GTS susceptibility gene. It is likely that most of these candidate genes tested are not involved in the

Future directions

Recent advances in cataloging human genetic polymorphisms, in addition to the decreasing cost of high-throughput SNP genotyping and the development of statistical methodology to analyze large sample sets in a rigorous manner, have made genome-wide association studies (GWASs) a feasible method for genetic studies of complex disorders [134]. Based on the hypothesis that a proportion of the genetic susceptibility for common diseases may be caused by common genetic variants that arose early in

References (163)

  • GradosMA et al.

    Latent class analysis of Gilles de la Tourette syndrome using comorbidities: clinical and genetic implications

    Biol Psychiatry

    (2008)
  • PaulsDL et al.

    Segregation and linkage analyses of Tourette's syndrome and related disorders

    J Am Acad Child Adolesc Psychiatry

    (1990)
  • PetekE et al.

    Disruption of a novel gene (IMMP2L) by a breakpoint in 7q31 associated with Tourette syndrome

    Am J Hum Genet

    (2001)
  • DonnaiD

    Gene location in Tourette syndrome

    Lancet

    (1987)
  • VerkerkAJ et al.

    CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder

    Genomics

    (2003)
  • BrettPM et al.

    The genetic susceptibility to Gilles de la Tourette syndrome in a large multiple affected British kindred: linkage analysis excludes a role for the genes coding for dopamine D1, D2, D3, D4, D5 receptors, dopamine beta hydroxylase, tyrosinase, and tyrosine hydroxylase

    Biol Psychiatry

    (1995)
  • LeeCC et al.

    Dopamine receptor D2 gene polymorphisms are associated in Taiwanese children with Tourette syndrome

    Pediatr Neurol

    (2005)
  • BrettP et al.

    Failure to find linkage and increased homozygosity for the dopamine D3 receptor gene in Tourette's syndrome

    Lancet

    (1993)
  • HebebrandJ et al.

    Tourette's syndrome and homozygosity for the dopamine D3 receptor gene. German Tourette's Syndrome Collaborative Research Group

    Lancet

    (1993)
  • de la TouretteG.

    Etude sur une affection nerveuse caracterisee par de l'indoordination motrice accompagnee d'echolalie et al copralalie

    Archives or Neurology

    (1885)
  • PaulsDL et al.

    Gilles de la Tourette's syndrome and attention deficit disorder with hyperactivity. Evidence against a genetic relationship

    Arch Gen Psychiatry

    (1986)
  • KiddKK et al.

    Familial pattern of Gilles de la Tourette syndrome

    Arch Gen Psychiatry

    (1980)
  • PaulsDL et al.

    Familial pattern and transmission of Gilles de la Tourette syndrome and multiple tics

    Arch Gen Psychiatry

    (1981)
  • PaulsDL et al.

    A family study of Gilles de la Tourette syndrome

    Am J Hum Genet

    (1991)
  • EapenV et al.

    Evidence for autosomal dominant transmission in Tourette's syndrome. United Kingdom cohort study

    Br J Psychiatry

    (1993)
  • WalkupJT et al.

    Family study and segregation analysis of Tourette syndrome: evidence for a mixed model of inheritance

    Am J Hum Genet

    (1996)
  • KanoY et al.

    A family study of Tourette syndrome in Japan

    Am J Med Genet

    (2001)
  • SmollerJW et al.

    Psychiatric genetics applications in clinical practice

    (2008)
  • FreemanRD et al.

    An international perspective on Tourette syndrome: selected findings from 3,500 individuals in 22 countries

    Dev Med Child Neurol

    (2000)
  • Mol DebesNM et al.

    Validation of the presence of comorbidities in a Danish clinical cohort of children with Tourette syndrome

    J Child Neurol

    (2008)
  • FreemanRD

    Tic disorders and ADHD: answers from a world-wide clinical dataset on Tourette syndrome

    Eur Child Adolesc Psychiatry

    (2007)
  • KarnoM et al.

    The epidemiology of obsessive-compulsive disorder in five US communities

    Arch Gen Psychiatry

    (1988)
  • WeissmanMM et al.

    The cross national epidemiology of obsessive compulsive disorder. The Cross National Collaborative Group

    J Clin Psychiatry

    (1994)
  • PolanczykG et al.

    The worldwide prevalence of ADHD: a systematic review and metaregression analysis

    Am J Psychiatry

    (2007)
  • PringsheimT et al.

    Understanding disability in Tourette syndrome

    Dev Med Child Neurol

    (2008)
  • BudmanCL et al.

    Rage attacks in children and adolescents with Tourette's disorder: a pilot study

    J Clin Psychiatry

    (1998)
  • PaulsDL

    The genetics of obsessive compulsive disorder: a review of the evidence

    Am J Med Genet C Semin Med Genet

    (2008)
  • PaulsDL et al.

    Gilles de la Tourette's syndrome and obsessive-compulsive disorder. Evidence supporting a genetic relationship

    Arch Gen Psychiatry

    (1986)
  • CurtisD et al.

    Autosomal dominant gene transmission in a large kindred with Gilles de la Tourette syndrome

    Br J Psychiatry

    (1992)
  • PaulsDL et al.

    A family study of obsessive-compulsive disorder

    Am J Psychiatry

    (1995)
  • LeonardHL et al.

    Tics and Tourette's disorder: a 2- to 7-year follow-up of 54 obsessive-compulsive children

    Am J Psychiatry

    (1992)
  • NestadtG et al.

    A family study of obsessive-compulsive disorder

    Arch Gen Psychiatry

    (2000)
  • ComingsDE et al.

    controlled study of Tourette syndrome. I. Attention-deficit disorder, learning disorders, and school problems

    Am J Hum Genet

    (1987)
  • KnellER et al.

    Tourette's syndrome and attention-deficit hyperactivity disorder: evidence for a genetic relationship

    J Clin Psychiatry

    (1993)
  • ORourke JA, Scharf JM, Stewart E, Platko J, Illmann C, Geller D, King RA, Leckman JF, Pauls D. The familial association...
  • SpencerT et al.

    Disentangling the overlap between Tourette's disorder and ADHD

    J Child Psychol Psychiatry

    (1998)
  • McMahonWM et al.

    Children at familial risk for Tourette's disorder: child and parent diagnoses

    Am J Med Genet B Neuropsychiatr Genet

    (2003)
  • RobertsonMM et al.

    Principal components analysis of a large cohort with Tourette syndrome

    Br J Psychiatry

    (2008)
  • ComingsDE et al.

    Detection of major gene for Gilles de la Tourette syndrome

    Am J Hum Genet

    (1984)
  • BaronM et al.

    Genetic analysis of Tourette syndrome suggesting major gene effect

    Am J Hum Genet

    (1981)
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    Supported in part by grants from the National Institute of Neurological Disease and Stroke, NS16648 and NS40024.

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