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The genetics of Tourette syndrome: A review
Open accessAbstract
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=3.8x10(-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.
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“a rare mutation in the gene SLITRK1 is associated with human TS [613,614].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [614]
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“In particular, correlation studies with cortical thickness may be informative as TS children were found to have larger prefrontal cortex volume, whereas those of TS adults were smaller.6,18 As LTP underlies learning, it would also be productive to combine iTBS studies with relevant cognitive tasks, such as the Probabi…”
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“Although it is widely accepted that genetic factors play a significant role in TS etiology, only a few genes have been suggested to render susceptibility to TS [O’Rourke et al., 2009; Paschou, 2013].”
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“However, research thus far indicates that ADHD is not increased in families with TS, which may suggest that the association is not because of shared susceptibility genes for those two disorders but possibly because of OCD or shared environmental factors [122, 123].”
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Tourette disorder spectrum maps to chromosome 14q31.1 in an Italian kindred
Breedveld, G. J., Fabbrini, G., Oostra, B. A., Berardelli, A., & Bonifati, V. (2010) · Neurogenetics · doi:10.1007/s10048-010-0244-7 · Cited by 28
Animal Models Recapitulating the Multifactorial Origin of Tourette Syndrome
Macrì, S., Onori, M. P., Roessner, V., & Laviola, G. (2013) · International review of neurobiology · doi:10.1016/b978-0-12-411546-0.00008-1 · Cited by 28
Involvement of astrocyte metabolic coupling in Tourette syndrome pathogenesis
de Leeuw, C., Goudriaan, A., Smit, A. B., Yu, D., Mathews, C. A., Scharf, J. M., Verheijen, M. H. G., & Posthuma, D. (2015) · European Journal of Human Genetics · doi:10.1038/ejhg.2015.22 · Cited by 26
Self-citationGenetic variation associated with the occurrence and progression of neurological disorders
Little, J., Barakat, C., Martino, R., Pringsheim, T. M., Tremlett, H. L., McKay, K. A., Lieshout, P. H. H. M. V., Walsh, S. J., Gomes, J., & Krewski, D. R. (2016) · NeuroToxicology · doi:10.1016/j.neuro.2016.09.018 · Cited by 28
Tourette's syndrome and other tic disorders
Rickards, H. E. (2010) · Practical Neurology · doi:10.1136/jnnp.2010.223685 · Cited by 26
“Family studies show that it is to a large extent heritable alongside an early onset form of OCD; large family pedigree studies have indicated that these two disorders cluster together but the commonest form of ADHD does not share genetic factors with Tourette's syndrome.”
BackgroundGagné, J. (2018) · Clinical Psychology Review · doi:10.1016/j.cpr.2018.09.005 · Cited by 26
Emotional development in children with tics: a longitudinal population-based study
Hoekstra, P. J., Lundervold, A. J., Lie, S. A., Gillberg, C., & Plessen, K. J. (2012) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-012-0337-y · Cited by 26
“Genetic studies have shown a shared underlying susceptibility between tics and childhood-OCD [25] and approximately one-third of the persons with Tourette’s Disorder also display symptoms of obsessive–compulsive behavior (OCB) and another third fulfil criteria for OCD [26].”
BackgroundMacrı̀, S., Onori, M. P., & Laviola, G. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.03.014 · Cited by 26
Abdulkadir, M., Londoño, D., Gordon, D., Fernandez, T. V., Brown, L. W., Cheon, K.-A. A., Coffey, B. J., Elzerman, L., Fremer, C., Fründt, O., et al. (2017) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-017-0808-8 · Cited by 25
“The strong heritability has led to a wide range of gene finding efforts, which initially, prior to the initiation of genome-wide association studies (GWAS) focused on family-based linkage and candidategene-based case–control studies [1, 2].”
BackgroundMethodInfluentialThe illnesses of Charles Darwin and his children: a lesson in consanguinity
Hayman, J., Álvarez, G., Ceballos, F. C., & Berra, T. M. (2017) · Biological Journal of the Linnean Society · doi:10.1093/biolinnean/blw041 · Cited by 24
The complex genetics of Gilles de la Tourette syndrome: implications for clinical practice
Ali, F., Morrison, K. E., & Cavanna, A. E. (2013) · Neuropsychiatry · doi:10.2217/npy.13.25 · Cited by 24
Social communication deficits and restricted repetitive behavior symptoms in Tourette syndrome
Eapen, V., McPherson, S., Karlov, L., Nicholls, L. E., Črnčec, R., & Mulligan, A. (2019) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s210227 · Cited by 25
Balance within the Neurexin Trans-Synaptic Connexus Stabilizes Behavioral Control
Clarke, R. A., & Eapen, V. (2014) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2014.00052 · Cited by 24
The genetic factors influencing the development of trichotillomania
CHATTERJEE, K. (2011) · Journal of Genetics · doi:10.1007/s12041-011-0094-6 · Cited by 23
Klimkeit, E., Rinehart, N., May, T., & Bradshaw, J. L. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-803678-5.00299-x · Cited by 23
Tic symptom dimensions and their heritabilities in Tourette’s syndrome
Haan, M. D., Delucchi, K., Mathews, C., & Cath, D. C. (2015) · Psychiatric Genetics · doi:10.1097/ypg.0000000000000084 · Cited by 20
“…of TS as estimated from small clinical twin studies (Price et al., 1985; Goetz and Tanner, 1990; Hyde et al., 1992; Wolf et al., 1996), from family studies (Pauls et al., 1991; O’Rourke et al., 2009) and, most recently, from genome-wide association studies (GWASs) (Davis et al., 2013) is up to 60%.”
BackgroundMethodBeetsma, D. J. V., van den Hout, M., Engelhard, I. M., Rijkeboer, M. M., & Cath, D. C. (2013) · Behavioural Neurology · doi:10.1155/2013/642487 · Cited by 18
Evaluation of the LIM homeobox genesLHX6andLHX8as candidates for Tourette syndrome
Paschou, P., Stylianopoulou, E., Karagiannidis, I., Rizzo, R., Tárnok, Z., Wolańczyk, T., Hebebrand, J., Nöthen, M. M., Lehmkuhl, G., Farkas, L., et al. (2012) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2012.00778.x · Cited by 18
“Although multiple genes and chromosomal regions have been implicated in TS etiology (see Grados 2010; O’Rourke et al. 2009; State 2011) the difficulty in replicating the original positive results, underlines the complexity and heterogeneity of the etiological background of the disorder.”
BackgroundGDNF gene is associated with tourette syndrome in a family study
Huertas‐Fernández, I., Gómez‐Garre, P., Madruga‐Garrido, M., Bernal‐Bernal, I., Bonilla‐Toribio, M., Martin‐Rodríguez, J. F., Cáceres‐Redondo, M. T., Vargas‐González, L., Carrillo, F., Pascual, A., et al. (2015) · Movement Disorders · doi:10.1002/mds.26279 · Cited by 18
“candidate genes such as various dopamine receptors, monoamine oxidase-A, the dopamine transporter gene, and other related genes, is unclear.(2,4) Mounting evidence has been noted about the involvement of the glutamatergic system in TS.”
BackgroundLiao, C., Vuokila, V., Catoire, H., Akçimen, F., Ross, J. P., Bourassa, C. V., Dion, P. A., Meijer, I. A., & Rouleau, G. A. (2022) · Communications Biology · doi:10.1038/s42003-022-03231-0 · Cited by 18
Behavioral Interventions for Children and Adults with Tic Disorder
Woods, D. W., Himle, M. B., Stiede, J. T., & Pitts, B. X. (2023) · Annual Review of Clinical Psychology · doi:10.1146/annurev-clinpsy-080921-074307 · Cited by 20
Genetic architecture of Tourette syndrome: our current understanding
Domènech, L., Cappi, C., & Halvorsen, M. (2021) · Psychological Medicine · doi:10.1017/s0033291721000234 · Cited by 18
The many faces of Gilles de la Tourette syndrome
Robertson, M. M., & Cavanna, A. E. (2009) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2009.09.001 · Cited by 17
“This special issue is enriched by up-to-date reviews on etiology, including the genetics of GTS [12] and the PANDAS hypothesis [13], imaging evidence for anatomical disturbances and neuroplastic compensation in persons with GTS [14], as well as functional neuroimaging in GTS [15].”
Web-based phenotyping for Tourette Syndrome: Reliability of common co-morbid diagnoses
Darrow, S. M., Illmann, C., Gauvin, C. A., Osiecki, L., Egan, C. A., Greenberg, E., Eckfield, M. B., Hirschtritt, M. E., Pauls, D. L., Batterson, J. R., et al. (2015) · Psychiatry Research · doi:10.1016/j.psychres.2015.05.017 · Cited by 16
Self-citationPediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus in Identical Siblings
Lewin, A. B., Storch, E. A., & Murphy, T. K. (2011) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2010.0085 · Cited by 16
“Twin studies also suggest a high concordance rate for tic disorders (Hyde et al. 1992; O’Rourke et al. 2009).”
Yasmeen, S., Melchior, L., Bertelsen, B., Skov, L., Debes, N. M., & Tümer, Z. (2013) · Psychiatric Genetics · doi:10.1097/ypg.0b013e328360c880 · Cited by 16
Copy number variation in Tourette syndrome
Scharf, J. M., & Mathews, C. A. (2010) · Neurology · doi:10.1212/wnl.0b013e3181e24161 · Cited by 16
Self-citationOnori, M. P., Ceci, C., Giovanni Laviola, A., & Macrı̀, S. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.03.023 · Cited by 15
Aripiprazole for the treatment of Tourette syndrome
Cox, J. H., & Cavanna, A. E. (2021) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2021.1893693 · Cited by 15
“The risk of TS in first degree relatives of people with TS is reported to be 10 to 100 times higher than the prevalence of TS in the general population [15].”
BackgroundGenetic animal models of Tourette syndrome: The long and winding road from lab to clinic
Cauchi, R. J., & Tárnok, Z. (2012) · Translational Neuroscience · doi:10.2478/s13380-012-0020-2 · Cited by 14
“In this regard, several association studies assessing a variety of biologically plausible candidate genes as well as linkage screens were undertaken to underpin TS susceptibility loci [34 - 37].”
BackgroundBansal, V., Mitjans, M., Burik, C. A. P., Linnér, R. K., Okbay, A., Rietveld, C. A., Begemann, M., Bonn, S., Ripke, S., de Vlaming, R., et al. (2018) · RePEc: Research Papers in Economics · Cited by 15
Predictive factors for familiality in a Danish clinical cohort of children with Tourette syndrome
Debes, N. M., Hjalgrim, H., & Skov, L. (2010) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2010.05.001 · Cited by 13
Unpacking Tourette Syndrome in Children: Insights into Prevalence and Comorbidities from NSCH Data
Gunturu, S., Saeidi, M., Alzein, O., Jafari, K., Salehi, M., & Jaka, S. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14051485 · Cited by 12
“The cortico-striato-thalamo-cortical circuitry, crucial for TS symptoms, interacts with neuro-transmitter systems that modulate immune responses, which could lead to a heightened inflammatory state [63,64].”
Analysis of SLITRK1 in Japanese patients with Tourette syndrome using a next-generation sequencer
Inai, A., Tochigi, M., Kuwabara, H., Nishimura, F., Kato, K., Eriguchi, Y., Shimada, T., Furukawa, M., Kawamura, Y., Sasaki, T., et al. (2015) · Psychiatric Genetics · doi:10.1097/ypg.0000000000000104 · Cited by 12
“Twin and family studies have provided strong evidence for the genetic nature of TS, whereas few putative susceptibility genes have been suggested to date (O’Rourke et al., 2009; Scharf et al., 2013).”
BackgroundRizwan, M., Shahid, N. U. A., Naguit, N., Jakkoju, R., Laeeq, S., Reghefaoui, T., Zahoor, H., Yook, J. H., & Mohammed, L. (2022) · Cureus · doi:10.7759/cureus.22449 · Cited by 12
Egan, C. A., Marakovitz, S. E., O’Rourke, J. A., Osiecki, L., Illmann, C., Barton, L., McLaughlin, E., Proujansky, R., Royal, J. D., Cowley, H., et al. (2012) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32107 · Cited by 12
“Multiple linkage regions and candidate genes have been reported for TS using both targeted and genome-wide approaches, but these findings have not been consistently replicated, and together only account for a small proportion of the genetic variance of TS [O’Rourke et al., 2009; Ercan-Sencicek et al., 2010; Sundaram e…”
BackgroundInfluentialSelf-citationTourette Syndrome and Tic Disorders
Tochen, L. S., & Singer, H. S. (2016) · Handbook of behavioral neuroscience · doi:10.1016/b978-0-12-802206-1.00048-9 · Cited by 11
Tourette Syndrome Risk Genes Regulate Mitochondrial Dynamics, Structure, and Function
Clarke, R. A., Furlong, T. M., & Eapen, V. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.556803 · Cited by 10
Beetsma, D. J. V., van den Hout, M., Engelhard, I. M., Rijkeboer, M. M., & Cath, D. C. (2014) · Behavioural Neurology · doi:10.1155/2014/753020 · Cited by 11
Metadata
- Authors
- O'Rourke, J. A., Scharf, J. M., Yu, D., & Pauls, D. L.
- Affiliations
- Harvard University (US)
- Corresponding author
- Pauls, David L.
- Venue
- Journal of Psychosomatic Research
- Publisher
- Elsevier BV
- Published
- 2009-12
- Volume
- 67
- Issue
- 6
- Pages
- 533-545
- ISSN
- 0022-3999 (ISSN-L)
- PMC
- PMC2778609
- OpenAlex
- W2041237576
- Cited by
- 212
- References
- 171
- Citations by year
- 2026: 3 · 2025: 31 · 2024: 2 · 2023: 4 · 2022: 6 · 2021: 10 · 2020: 16 · 2019: 6 · 2018: 5 · 2017: 10 · 2016: 9 · 2015: 13 · 2014: 13 · 2013: 21 · 2012: 23
- FWCI
- 2.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Psychosomatic Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS40024, R01NS016648, U01NS040024, R01NS040024, NS-16648)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Tourette syndrome, genetic etiology, attention deficit hyperactivity disorder, obsessive-compulsive disorder, linkage analysis, SLITRK1, chromosomal translocation, candidate genes, genome-wide association study, genetic heterogeneity
- MeSH terms
- Alleles, Attention Deficit Disorder with Hyperactivity, Genotype, Tourette Syndrome, Humans, Genetic Linkage, Obsessive-Compulsive Disorder, Genome-Wide Association Study
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