For a long time, Tourette Syndrome (TS) has been a little-known disorder, frequently misunderstood and far too often mocked. Recently, however, with high-profile individuals like Lewis Capaldi and Billy Eilish speaking openly about their own diagnoses, TS has become a topic of frequent discussion, interest, and, I hope, better understanding.

Tourette Syndrome is a neurological disorder characterised by the presence of tics. Tics are the production of involuntary or uncontrolled movements (termed motor tics), or sounds (termed vocal tics). The tics must be present for more than 12 months to be diagnosed with TS (American Psychiatric Association, 2016). TS affects approximately 1 in 100 children and adolescents (Robertson et al., 2017).

For most people, TS starts during early childhood and characteristically waxes and wanes over time (Robertson et al., 2017). This means people often find that over weeks and months, tics can get slightly better or worse. Tics can also change from hour to hour or even minute to minute, with strong emotions such as stress, anxiety and excitement often making them worse.

While some people’s TS may improve or even disappear completely as they progress to adulthood, many people with TS have their symptoms for life (Groth et al., 2017). Tics at their worst can be debilitating – vocal tics can lead to communication issues and motor tics can cause problems with writing and walking, sometimes leading to extreme pain and discomfort. Coprolalia and copropraxia, swearing tics, although often thought to be hallmarks of the condition, are less common than many people think, affecting approximately 15% and 5% of people, respectively (Freeman et al., 2009).

It is well established that few people live solely with TS – over 85% also have other commonly occurring conditions, like autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), anxiety and depression (Hirschtritt et al., 2015).

Jain et al. (2023) aimed to investigate the association between TS and several other factors, like sociodemographics, and other disorders to help further our understanding of TS. They also aimed to identify factors that may be causally linked to the development of Tourette Syndrome.

Methods

First, the authors worked to define cases of TS using polygenic risk score (PRS). This is a technique used to calculate one’s genetic risk of having a diagnosis of TS or not. The PRS was calculated using a recent meta-analysis genome-wide association study (GWAS). Here, the authors looked at genetic data from over 6,000 individuals with TS and compared them to individuals without TS to see what genes may be significant in discerning between the two groups.

The final step was then to conduct a phenome-wide association study (PheWAS). This is a type of analysis that looks for an association between the genetic risk of having TS (the PRS) and a large number of other variables. In total, the authors looked at over 2,200 different variables from a large data set, the UK Biobank, which included more than 330,000 individuals. Jain et al. (2023) looked for associations between TS and mental health disorders, physical health disorders, social factors and biomarkers. They also conducted two further analyses:

1. First, they compared the associations found in TS between men and women.
2. Second, they compared the significant associations found for TS to the associations found for other, often co-morbid disorders, including OCD, attention-deficit/hyperactivity disorder (ADHD) and ASD.

Results

Associations between TS and other factors

This study found some significant (with p values less than 0.05) associations between the PRS for Tourette Syndrome and:

• Mental health outcomes such as depression and anxiety disorder.
• Physical health conditions such as connective tissue disorders, type 2 diabetes, heart palpitations, and several pain-related conditions, including back, neck, shoulder and hip pain. TS was also associated with poorer overall self-reported health.
• Sociodemographic outcomes such as high levels of deprivation and poorer educational and employment attainment.
• And elevated levels of one biomarker, glycated haemoglobin (an indicator of sugar levels in the blood).

Differences between sexes

With rates of TS in men often reported to be approximately four times higher than that seen in women (Johnson et al., 2023), you may have predicted a higher PRS generally for men. Interestingly, this was not observed in the current study, where there were no differences in PRS score distributions reported between sexes. Jain et al. (2023) reported a number of shared associations between the sexes, including associations with depressive episodes, back pain and poorer educational attainment. But, there were also some unique differences in associations between the sexes. For example, in men only, there was a significant association with certain mental health traits such as being ‘highly strung’ and neuroticism, as well as physical health associations, including type 2 diabetes and heart palpitations. In women only, there was an association with respiratory system diseases.

Comparison to other related conditions

Unsurprisingly, there was much overlap between the significant TS-related associations and those found for ADHD, ASD and OCD. This was particularly the case for outcomes related to cognition, mental health traits and, interestingly, one physical health trait, type 2 diabetes. Because of this high degree of overlap, the authors suggest that some of the associations seen in TS may be due to the co-occurrence of these other conditions. Interestingly, TS was the only condition that was found to be negatively associated with educational outcomes – ASD and OCD were associated with better outcomes.

Conclusions

In summary, the genetic risk of TS was found to be associated with several mental and physical health conditions, many of which were also seen in other neurodevelopmental disorders like ADHD, ASD, and OCD. These differences also appeared to be sex-specific for certain conditions.

The authors concluded:

Our results suggest that it is important to consider a broad range of mental health, general health, and even sociodemographic outcomes associated with TS and other neurodevelopmental disorders to shed light [on] the complex [causes] and related pathways underlying these conditions.

Strengths and limitations

This study has many strengths. First, the methods are a great example of large genetic data analysis, with up-to-date techniques being utilised. Secondly, the use of the UK Biobank dataset means there is a large number of people included in the analysis (over 330,000) and a vast number of factors being considered, both of which is important for such exploratory work.

When comparing cases to controls, the study can only be as good as the technique used to define these groups. Here, the authors have used the PRS calculated from GWAS. GWAS for TS are in relative infancy compared to other conditions. The GWAS used here included just over 6,000 individuals, but the number of individuals has since grown and currently sits nearer to 14,000. As a comparison, the GWAS for schizophrenia sits at close to 80,000 (Trubetskoy et al., 2022). The larger the population size, the greater the reliability and consistency of the genes highlighted. The genes highlighted from GWAS so far in studies with TS have often changed when repeated with larger population sizes, with little consistency. As such, defining cases using these GWAS may continue to be misleading until the GWAS population size is much larger. However, the polygenic risk scoring using the GWAS from this study has previously demonstrated a statistically significant ability to predict TS status in a novel cohort. Unfortunately, due to there being no participants with an International Classification of Diseases-10 diagnosis of TS in the UK Biobank, it was not possible to validate its accuracy in this case. Using PRS also has other limitations. While TS is a highly inheritable condition with concordance between monozygotic twins at 53%, this study could not capture any factors that impact whether those that have genetic risk do or do not develop the disorder. Despite these limitations, the techniques used here were the best currently available for identifying TS cases.

A general criticism of PRS/GWAS is that the data is disproportionately based on white European genetic data, so when you extrapolate to the generally diverse population, it may be unrepresentative or even inaccurate. This is not unique to this study, but it is something the field will have to address.

Implications for practice

This study has confirmed many previously reported associations, such as a link between TS and other conditions like anxiety and depression. We also know that over 90% of people with TS suffer from pain secondary to their tics, and epidemiological studies have shown higher rates of metabolic and cardiovascular outcomes in those with TS (Fernández de la Cruz and Mataix-Cols, 2020) – findings that are further supported by the current paper.

Future research

This study identified one biomarker associated with TS, glycated haemoglobin. Unfortunately, this was not commented on much in the paper, but identifying biomarkers from GWAS and PheWAS studies can be fruitful for further causal research.

The lack of sex differences in this study was also a novel finding. This is in direct contrast to previous studies, which widely report differences in rates between males and females. This suggests that there might be sex-chromosome differences or environmental factors influencing actual prevalence.

Finally, until more robust TS GWAS with more data from a larger participant pool become available, it will remain difficult to draw strong conclusions from studies like the current investigation.

Physical health

This paper has further highlighted the poorer longer-term health outcomes that are all too often a reality for people with TS. It is important for clinicians assessing and treating those with TS, to make sure appropriate health monitoring, advice, and interventions are offered to the community.

Educational

Another interesting finding was that the poorer educational outcomes were specific to TS, and not seen in other conditions such as OCD or ASD. I hope this highlights the specific need of those with TS and, specifically, the need for more tailored interventions and support.

Final thoughts

The paper indirectly references what is arguably the largest problem facing the TS community, which is poor access to diagnoses and treatment. It is surprising that among the cohort of 333,000, not one person reported having a labelled diagnosis of TS. As the authors also assert, with a prevalence rate of 0.6%, you would expect nearly 2,000 of these individuals to have undiagnosed TS. This is a story I personally hear time and time again: people are left waiting, desperate for a diagnosis and with little to no access to treatment. In a recent survey by Tourettes Action, the largest UK charity for TS, over 50% of people wait for over a year for an appointment, and nearly 20% wait for over three years. Perhaps most disheartening of all is that over half of people who eventually get assessed are given a diagnosis and discharged in the same appointment, being offered no ongoing support or treatment.

For both research and, ultimately, the quality of life of people living with TS to improve, we must first address the current widespread issue of a lack of access to assessment and treatment.

Statement of interests

Ed lives with Tourette Syndrome himself and is the Vice-chair of Tourettes Action Charity, the UK’s largest Tourette Syndrome charity.

Links

Primary paper

Jain P, Miller-Fleming T, Topaloudi A, et al. Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome. Transl Psychiatry. 2023 Feb 23;13(1):69. doi: 10.1038/s41398-023-02341-5

Other references

Fernández de la Cruz, L. and Mataix-Cols, D. (2020) ‘General health and mortality in Tourette syndrome and chronic tic disorder: A mini-review’, Neuroscience and Biobehavioral Reviews, 119, pp. 514–520. Available at: https://doi.org/10.1016/j.neubiorev.2020.11.005

Freeman, R.D. et al. (2009) ‘Coprophenomena in Tourette syndrome’, Developmental Medicine & Child Neurology, 51(3), pp. 218–227. Available at: https://doi.org/10.1111/j.1469-8749.2008.03135.x

Groth, C. et al. (2017) ‘Course of Tourette Syndrome and Comorbidities in a Large Prospective Clinical Study’, Journal of the American Academy of Child & Adolescent Psychiatry, 56(4), pp. 304–312. Available at: https://doi.org/10.1016/j.jaac.2017.01.010

Hirschtritt, M.E. et al. (2015) ‘Lifetime Prevalence, Age of Risk, and Genetic Relationships of Comorbid Psychiatric Disorders in Tourette Syndrome’, JAMA Psychiatry, 72(4), p. 325. Available at: https://doi.org/10.1001/jamapsychiatry.2014.2650

Johnson, K.A. et al. (2023) ‘Tourette syndrome: clinical features, pathophysiology, and treatment’, The Lancet Neurology, 22(2), pp. 147–158. Available at: https://doi.org/10.1016/S1474-4422(22)00303-9

Robertson, M.M. et al. (2017) ‘Gilles de la Tourette syndrome’, Nature Reviews Disease Primers, 3(1), pp. 1–20. Available at: https://doi.org/10.1038/nrdp.2016.97

Trubetskoy, V. et al. (2022) ‘Mapping genomic loci implicates genes and synaptic biology in schizophrenia’, Nature, 604(7906), pp. 502–508. Available at: https://doi.org/10.1038/s41586-022-04434-5

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