Genetics of Tourette Syndrome Part I
In this three-part series, I am introducing a brief history and phenotype of Gilles de la Tourette Syndrome. Subsequently, I will survey initial hypotheses about Tourette’s heritability, and twin and family studies.
Table of Contents:
- Initial Genetic Hypotheses
- Twin Studies
- Family Studies
Tourette Syndrome (TS) neurodevelopmental disorder affecting primarily children and adolescents, with 0.3–1.0% lifetime prevalence, significantly affecting their quality of life and in some cases causing a life-long disability (Elstner et al., 2001). Neurobiologically, TS causes marked abnormalities in Cortico-Striato-Thalamo-Cortical (CTSC) circuits, which are known to regulate control of motor, behavioral, and cognitive processes (Singer & Minzer, 2003), but the exact biology and pathogenesis of this disorder remains obscure.
TS was first described by Georges Gilles de la Tourette in 1885, in a collection of case histories characterized by the TS symptomatology — including involuntary movements, repetition of speech, and obscene language. The very first clinical case of the TS was likely documented by Jean-Marc Gaspard Itard in 1825, where Itard describes Marquise de Dampierre clinical case of motor and vocal tics (Walusinski & Féray, 2020; Yorston & Hindley, 1998).
Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) defines TS as a neurodevelopmental, motor, tic disorder. Diagnostic criteria for TS are: (A) both multiple motor and at least one vocal tic present at some point during the course of illness, (B) persistent for at least 1 year, regardless of frequency, (C) onset before the age of 18, and (D) absence of substance effects and other medical conditions which could explain the symptoms (APA, 2013). Tic is defined as a sudden, rapid, recurrent, and nonrhythmic motor movement or vocalization.
There are actually for specific diagnostic categories within this cluster: TS, Persistent (Chronic) Motor or Vocal Tic Disorder (PMVT) — which is characterized by the presence of either motor or vocal tics, Provisional (Transient) Tic Disorder (PTD) — which is characterized by tics present for less than a year, and other (un)specified tic disorders. The former three disorders may be phenotypically considered a severity spectrum of tic disorders, possibly due to aggregate effect of risk-increasing genetic variants (Figure 1).
Figure 1 represents the relationship between PTD, PMVT, and TS symptomatology, as well as a hypothesized polygenic effect on these disorders. In other words, these three disorders within the tic disorder cluster may be caused by the same pathogenic genetic variants. However the precise disorder a patient is suffering from may be a result of either aggregation of specific number of these pathogenic variants and/or interaction between some specific pathogenic veriants. In the subsequent sections, I will discuss the history of TS genetics.
2. Initial Genetic Hypotheses
Historically speaking, some of the most important tools in mapping disorders afflicting humans and making inferences about their heritability include comprehensive tracking of family history and pedigrees. Despite initial suggestions on TS heritability were made by Gilles de la Tourette himself, the very first published familial instance of TS came about in 1973 where three instances were noted in a Connecticut family (Friel, 1973). Two sisters had TS and out of their 6 children, 3 had motor tics only, and 1 had TS. This case history supports the hypothesis that TS and less severe tic disorders might be both pathologically and genetically related (see Figure 1). Below, we will review two types of studies commonly used to lay foundational knowledge about genetics and heritability of disorders: twin and family studies.
3. Twin Studies
Twin studies are very effective for determining potential genetic contributions to disease development. Specifically, studying disease occurrence in monozygotic twins (MZT) and dizygotic twins (DZT) offers a unique opportunity to estimate disease heritability. Additive genetic variance [A] denotes the variance resulting from the sum of allelic effects across the genome, and it can be estimated from twin data, which can also be used to estimate shared environmental variance [E] and residual variance [R] (Grasby et al., 2017). Family data involving twins usually provide valuable information because MZT share 100% of segregating DNA and DZT twins share 50% of segregating DNA.
Definitionally, the three variances add up to 1:
A + E + R = 1
Additionally, if reared together, the correlation between MZT [r₁] and DZT [r₂] can be written as:
r₁ = A + R
r₂ = 0.5 A+ R
Subsequently, additive genetic and residual variances can be derived:
A = 2(r₁ - r₂)
R =2r₂ - r₁
E = 1 - A - R= 1 - 2r₁ + 2r₂ - 2r₂ + r₁ = 1 - r₁
These equations represent basic heritability estimate model. However, utilization of structural equation modelling and additional variables from a more refined study allows optimized heritability estimates.
In one twin study, concordance rates of TS were observed to be 53% in MZT and 8% in DZT (Price et al., 1985). In another study of MZT, Hyde et al. (1992) have reported TS concordance rate of 56% and tic concordance rate of 94%. Zilhão et al. (2016) conducted a large study on the Netherlands Twin Register and derived heritability estimates of between .25 and .37, dependent on phenotypic definitions.
These findings are consistent with genetics as a strong driver of TS pathology, notable but incomplete penetrance for the risk variants, and a potential for both de novo and inherited genetic etiopathogenesis.
4. Family Studies
Unlike twin studies, family studies examine broader pedigrees to determine a potential for genetic effects, including siblings, parents, and other relatives. Modern methodologies can utilize genetic information to estimate heritability, however these estimates have been traditionally determined by pedigree relationships as rich genetic data are relatively recent tool. One of the most fundamental assumptions of heritability estimates is that quantitative trait [σₜ²] can be partitioned into independent genetic [σₐ²] and environmental [σₑ²]components, whereas the genetic [σₐ²] component can be furthermore partitioned into additive (polygenic) genetic variance [σₚ²], dominance variance [σᵣ²], and an epistatic variance [σᵢ²] (Bochud, 2017).
Mathematically, these can be represented as:
σₜ² = σₐ² + σₑ²
σₐ² = σₚ² + σᵣ² + σᵢ²
σₜ² = σₚ² + σᵣ² + σᵢ² + σₑ²
Using the variables above, we can estimate broad sense heritability [H²] which accounts for the total genetic contribution to phenotype variance, and narrow sense heritability [h²] which accounts for the additive (polygenic) genetic contribution to phenotype variance:
H² = σₐ² / σₜ²
h² = σₚ² / σₜ²
Similarly to twin studies, in family studies we also use additive genetic variance to estimate heritability. Hence, all the subsequent heritability estimates will be narrow-sense heritability estimates, or h².
Pauls et al. (1991) have conducted a study examining rates of TS, PMVT, and Obsessive-Compulsive Disorder (OCD) in relatives of TS patients. They concluded there was strong support for the hypothesis that OCD is etiologically related to TS and chronic tics, and that TS is inherited as a highly penetrant, sex-influenced, autosomal dominant trait. Subsequent studies have attempted to validate this pattern of inheritance, however with not much success. Eventually, the evidence suggested non-dominant and mixed model of inheritance (Walkup et al., 1996; Hasstedt et al., 1995; Eapen, Pauls, & Robertson, 1993; Pauls & Leckman, 1986).
Recently, a population cohort, multigenerational family study of 4826 TS and PMVT cases has concluded that tic disorders cluster in families primarily due to genetic factors and are among the most heritable neuropsychiatric conditions, with heritability estimate h² of 0.77 (Mataix-Cols et al., 2015).
Collectively, family studies suggest substantial genetic component to TS and related tic disorders, as well as non-Mendelian inheritance.
In this first part of three in the Genetics of Tourette Syndrome series, I have broadly covered history of TS and initial related genetic studies. An important takeaway point is that TS is highly related to other tic disorders, which can collectively be viewed as severity spectrum from both phenotypic and genotypic perspectives. Another important point is that tic disorders have a strong genetic component, but are polygenic non-Mendelian traits. In the subsequent part, I will review initial attempts to identify specific genetic variants and loci which may predict TS and tic disorder phenotypes.
APA American Psychiatric Association
CTSC Cortico-Striato-Thalamo-Cortical circuits
DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5th edition
DZT Dizygotic Twins
MZT Monozygotic Twins
TS (Gilles de la) Tourette Syndrome
OCD Obsessive-Compulsive Disorder
PMVT Persistent (Chronic) Motor or Vocal Tic Disorder
PTD Provisional (Transient) Tic Disorder
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- Eapen, V., Pauls, D. L., & Robertson, M. M. (1993). Evidence for Autosomal Dominant Transmission in Tourette’s Syndrome. British Journal of Psychiatry, 162(5):593–596. DOI: doi.org/10.1192/bjp.162.5.593
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