While some families have multiple people affected with TS, other families have only one member affected. What is the evidence that Tourette syndrome is genetic?
By Gary A. Heiman Ph.D. Department of Genetics, Rutgers, The State University of New Jersey.
Evidence from many studies, including family studies and twin studies, strongly suggests a genetic contribution causing Tourette Syndrome (TS) and other chronic tics disorders (CTD). These studies also suggest a biological relationship between TS and other associated conditions, particularly obsessive-compulsive disorder (OCD) and ADHD. However, despite strong evidence for a genetic contribution, progress in the identification of specific risk genes has been, until quite recently, halting. Research findings from our group, the Tourette International Collaborative Genetics (TIC Genetics), and others are beginning to make significant strides in understanding the genetic causes of TS and associated conditions. This brief article summarizes what we have learned about the genetics of TS from research.
Family studies are a study design that asks the question, “Is this disorder familial?” That is, does it “run in families?” Basically, these studies compare the rate of a disorder in relatives (e.g., parents, siblings, children) of someone with and someone without the disorder. If the rate of the disorder is higher in relatives of someone with the disorder than in relatives of someone without the disorder, that disorder is thought to be familial. Through many years and in various populations, family studies have consistently shown that TS is familial and that other CTD seem biologically related. Compared with relatives of individuals without TS (controls), the relatives of individuals with TS also have higher rates of TS and they also have higher rates of other CTD. Thus, TS and CTD runs in families. Family studies have also shown that other neuropsychiatric disorders including OCD, ADHD, and autism spectrum disorders (ASD) are increased in the relatives of individuals with TS, suggesting that a biological shared relationship could exist. Family studies can also be used to calculate familial recurrence risks to relatives. Recurrence risk is the chance that a disorder in one family member will reoccur in another family member. We recently published an article showing that the recurrence risk for any first-degree relative (i.e., parents, siblings, or children) is approximately 30%.
Twin studies are conducted to disentangle the genetic and non-genetic factors which cause a disorder. In twin studies, the presence of the same disorder in both members of the twin pair (also called concordance) is assessed. A disorder with a genetic component would be expected to exhibit a higher concordance in identical twins than in non-identical twins. In TS and other CTD, only a few twin studies have been conducted and all support a genetic contribution causing these disorders. Twin studies have also suggested a shared genetic etiology (cause) between TS and OCD, but the relationship between TS and ADHD and/or ASD is less clear.
Molecular genetics studies are then conducted to determine where the gene(s) that increase risk for the disorder are located within the genome. There are different types of molecular study designs and each has a specific underlying hypothesis as to the genetic architecture causing the disorder. Some studies hypothesize that many common variants/mutations (changes in the DNA), each with a small increase risk, act in concert to cause the disorder. Other types of molecular studies search for rare variants in genes that can individually cause the disease. While research has consistently demonstrated a significant genetic contribution, the role of genes in TS, is currently not well understood.
In the last few years, the TIC Genetics group published two articles that have led to significant progress in understanding the genetic causes of TS. The first was published in 2017 (https://www.rutgers.edu/news/damaged-genes-considered-high-risk-developing-tourette-syndrome-identified) while the second was published in 2018 (https://medicalxpress.com/pdf457781845.pdf). In these studies, we purposely selected families in which the child had TS and the parents did not. We were trying to find new mutations that are not inherited from parents, but rather occur spontaneously in a particular egg or sperm or at conception. While TS is often inherited (passing from parent to child) as a consequence of pre-existing mutation in a gene, in some cases it might result from a new mutation in a gene.
The results of these two publications are important in several ways. First, we showed that many genes are involved in causing TS. It is not like cystic fibrosis, Tay-Sachs, or sickle cell anemia in which each disorder is caused by mutations in one gene. Instead, we estimated that over 400 genes that, when they have a damaging mutation (one that disrupts protein function), can cause TS. There are probably other genes that work in combination to cause TS but that is even more complicated to discern. Thus, the genetics of TS is like other neuropsychiatric (or neurodevelopmental) disorders in that it is caused by mutations in many different genes. This is an important step forward in our understanding. Second, we estimated that about 12 percent of TS cases likely involve new mutations, but these new mutations in one generation can be “passed down” in the next generation. Thus, in some families, you might see only one person with the disorder, but in other families, there could be multiple individuals with the disorder. Third, we found a few genes with new damaging mutations that each occurred in different families. This is like lightening striking twice and therefore, very notable. Lastly, we found that some of these risk genes are pointing “cell polarity” as a possible mechanism in causing TS. A disruption in cell polarity could affect how neurons are getting to the correct location and make correct connections during neurodevelopment. That is, cell polarity could be how brain development is disrupted in TS.
As an aside, many of the NJCTS families who participated previously were part of this important effort and I want to thank them. We could not have made this progress without you.
These results provide a framework for future research into the causes and treatment of TS. We now understand that TS is the result of mutations in different genes that result in similar symptoms. This means that the cause of TS in one family is likely to be different from the cause in another family. So, testing individuals to determine if they have a TS-risk mutation will be complicated. However, these many genetic factors likely work within a smaller number of biological pathways in the brain (e.g., cell polarity). As we find more of these TS-risk genes, we can determine how these genes interact in biological pathways during brain development and within the adult brain. After such TS pathways are identified, it may be possible to develop drugs that correct the malfunctioning pathways, thus alleviating symptoms.
The next steps are to find more of these risk-raising genes so that we can better understand which pathways or networks are involved so that tailored treatments can be developed. To find these genes, many more participants and their blood samples are needed. TIC Genetics is looking to recruit many more families and we are especially looking for families in which only one person is affected with TS or another CTD and both parents are available to participate.
All samples are initially analyzed by TIC Genetics Study researchers and later made available by National Institutes of Health (NIH) to qualified scientists around the world. All information is kept strictly confidential. To inquire about becoming a part of these breakthrough efforts to advance TS research by the TIC Genetics team, please email: firstname.lastname@example.org. We can do everything by mail and phone.
The TIC Genetics study is supported by grants from the New Jersey Center for Tourette Syndrome (NJCTS: https://njcts.org/) and from the National Institute of Mental Health.
We greatly appreciate the participation of many New Jersey families in the past and may have an opportunity to reach more at the NJCTS Family Retreat Weekend! We hope you will participate!
Gary A. Heiman, PhD
Associate Professor and Vice Chair
Department of Genetics
Rutgers, The State University of New Jersey