Twin Studies and Heritability Estimates

Twin studies have been instrumental in establishing the genetic basis of TS. These studies compare concordance rates (the proportion of twin pairs where both twins have TS) between monozygotic (MZ or “identical”) twins, who share nearly all their genetic material, and dizygotic (DZ or “fraternal”) twins, who share about 50%. Early twin studies found that MZ twins had much higher concordance rates for TS (53%–77%) compared to DZ twins (8%–23%). ^, These findings suggest that genetic factors play a significant role in the development of TS.

Familial Aggregation

Family studies have consistently shown that TS runs in families, providing additional evidence for the genetic basis of the disorder. First-degree relatives (parents, siblings, and children) of individuals with TS have a much higher probability of developing the disorder compared to the general population. The rate of TS in first-degree relatives is estimated to be at least 10 times higher than the population prevalence, depending on the study and diagnostic criteria applied. ^,

Moreover, family studies have shown that conditions related to and often co-occurring with TS, such as other chronic tic disorders, ADHD, OCD, and other neuropsychiatric conditions, are more common among relatives of individuals with TS. This suggests that shared genetic factors may contribute to the development of these conditions. The phenomenon responsible for this is pleiotropy, where genes can influence multiple traits or conditions that may seem unrelated. In the case of TS, pleiotropy may increase the risk of developing not only TS but also its commonly co-occurring conditions, such as ADHD and OCD. This helps explain why these disorders tend to cluster within families.

Heritability Estimates

Heritability estimates, representing the proportion of variation in a trait that can be attributed to genetic factors, have been derived from twin and family studies. For TS, heritability estimates range from 50% to 80%, ^, indicating that genetic factors contribute substantially to the risk of developing the disorder. However, the fact that heritability estimates are less than 100% and there can be a lack of concordance between MZ twins suggests that environmental factors may also play a role in TS.

Segregation Analyses and Mode of Inheritance

Segregation analyses have investigated how TS is inherited within families. Early studies suggested that TS might follow a Mendelian autosomal dominant pattern of inheritance with incomplete penetrance. ^, This means that a single copy of a risk gene inherited from one parent would be enough to cause TS, but not everyone who inherits the risk gene would develop the disorder.

However, later studies challenged this simple model of inheritance, suggesting that the genetic basis of TS is more complex. The current understanding is that TS is influenced by multiple genetic variants with various individual effect sizes and environmental factors that may interact with these genetic susceptibilities. This complex mode of inheritance is further supported by the observation that TS does not follow a clear Mendelian inheritance pattern in most families.

In summary, twin studies, family studies, and segregation analyses have consistently provided strong evidence for the genetic basis of TS. However, the incomplete concordance rates in identical twins, the familial co-occurrence of related conditions, and the complex mode of inheritance suggest that the development of TS involves a complex interplay among multiple genetic and environmental factors.

Chromosomal Abnormalities

Rare chromosomal abnormalities, such as translocations (exchange of genetic material between chromosomes) and deletions (loss of a portion of a chromosome), have been reported in some individuals with TS. These abnormalities have helped researchers identify potential candidate regions and genes that may contribute to the development of the disorder.

For example, a rare translocation involving chromosomes 7 and 18 was found in a family with multiple members affected by TS. This finding suggested that genes in these regions may be involved in the disorder’s pathogenesis. Additionally, chromosomal abnormalities on chromosome 18q22 have been identified in patients with chronic tics and OCD, mapping close to the chromosome 18 breakpoint in the family with the 7;18 translocation. ^,

However, it is important to note that chromosomal abnormalities are found in only a small proportion of individuals with TS, and their causal role in the disorder remains unclear. In many cases, these abnormalities may represent rare, highly penetrant factors contributing to the development of TS in specific individuals or families rather than being a common cause of the disorder in the general population.

Candidate Gene Association Studies

Numerous candidate gene association studies have been conducted to investigate the role of specific genes in TS. These studies have primarily focused on genes involved in neurotransmitter systems, such as dopamine and serotonin, which are thought to play a role in the pathophysiology of TS.

Dopaminergic genes, including DRD2 ( dopamine receptor D2 ), DRD4 ( dopamine receptor D4 ), and DAT1 ( SLC6A3, solute carrier family 6 member 3 ), have been among the most extensively studied candidates. ^{, ,} Some studies have reported associations between specific variants in these genes and TS, but the results have been inconsistent across different populations and study designs. Similarly, studies of serotonergic genes, such as SLC6A4 (solute carrier family 6 member 4, particularly the serotonin-transporter-linked promotor region) and HTR2A (5-hydroxytryptamine receptor 2A), have yielded mixed results.

Other candidate genes that have been investigated in TS include two genes first identified by chromosomal alterations, SLITRK1 ( SLIT and NTRK like family member 1 ) and CNTNAP2 ( contactin associated protein 2 ), and genes involved in immune function, neurodevelopment, neuroendocrine, and metabolic pathways. ^{, , ,} While some studies have suggested associations between these genes and TS, the findings have not been consistently replicated, and their role in the disorder remains uncertain.

Candidate gene association studies may be inconsistent due to several factors, including small sample sizes, heterogeneity in TS phenotypes, and the disorder’s complex genetic architecture. ^, As a result, the specific contributions of individual genes to TS risk remain largely unknown. Larger, well-powered studies and more advanced genetic methods are needed to identify genes in TS.

Genetic Linkage Studies

Genetic linkage studies have been used to identify chromosomal regions that may harbor genes contributing to TS susceptibility. These studies investigate the cosegregation of genetic markers with the disorder in families, aiming to locate regions of the genome that are shared more often than expected by chance among affected individuals.

Several linkage studies have implicated regions on chromosomes 2, 3, 4, 5, 7, 8, 11, 15, and 17 in TS. However, the specific genes in these regions contributing to TS risk have not been conclusively identified. The lack of consistent findings across linkage studies may be due to TS’s genetic heterogeneity, the presence of phenocopies (individuals with TS who do not carry the familial risk alleles), and the limited power of linkage analysis to detect genes with small individual effects.

One notable exception is the identification of a rare mutation in the HDC (histidine decarboxylase) gene, located within a linkage region on chromosome 15. This mutation was found to segregate with TS in a large family and was shown to disrupt the function of the histidine decarboxylase enzyme, which is involved in the production of histamine. This finding suggests that altered histaminergic neurotransmission may contribute to the pathogenesis of TS in some cases, although further research is needed to confirm this hypothesis. ^,

Genome-wide Association Studies

Genome-wide association studies (GWAS) have revolutionized the field of complex disease genetics by allowing researchers to identify genetic risk factors across the entire genome without any prior hypotheses about the underlying biology of the disorder. ^, These studies compare the frequencies of single nucleotide polymorphisms (SNPs) between large groups of individuals with and without TS, aiming to identify genetic variants associated with TS risk.

In TS, GWAS identified loci surpassing the genome-wide statistical significance threshold, highlighting the genes FLT3 ( fms related receptor tyrosine kinase 3 ) and NR2F1 ( nuclear receptor subfamily 2 group F member 1 ), both implicated in neurodevelopment. However, the effect sizes of individual loci identified in GWAS are typically small, with odds ratios ranging from 1.1 to 1.3. This suggests that TS risk is influenced by a combination of many genetic variants, each with a small individual effect. ^, Moreover, these GWAS signals have yet to be replicated in independent samples.

One limitation of GWAS in TS has been the relatively small sample sizes compared to studies of other complex disorders. ^, Larger cohorts are needed to increase the statistical power to detect additional risk variants and to validate the findings of previous studies. The Psychiatric Genomics Consortium has demonstrated the importance of large sample sizes in identifying hundreds of risk loci for other psychiatric disorders, such as schizophrenia, bipolar disorder, autism spectrum disorder (ASD), and ADHD.

Additionally, GWAS primarily capture common genetic variants and may not detect rare variants with larger effect sizes that contribute to TS risk. ^, Identifying these rare variants requires different approaches, such as whole-exome and whole-genome sequencing, ^, discussed in a later section.

Polygenic Risk Scores

Although individual SNPs identified by GWAS may have small effect sizes, their combined effects across the genome can be substantial. Polygenic risk scores (PRS) aggregate the effects of multiple genetic variants to assess an individual’s overall genetic risk for a disorder. ^,

In TS, PRS have been shown to predict the presence of tics in independent cohorts ^, and to correlate with tic severity and the presence of co-occurring disorders. These findings support the idea that TS exists on a spectrum with other tic disorders and that common genetic variants contribute to the risk of developing tics. ^,

However, PRS alone do not fully capture an individual’s genetic risk for TS, and their clinical utility is currently limited. The accuracy of PRS depends on the size and quality of the GWAS from which they are derived, and larger studies are needed to refine these scores and improve their predictive ability. Additionally, studies have shown that rare variants also play a significant role in TS risk. ^, Future research will need to integrate different types of genetic variation to better understand the complex genetic architecture of TS. ^,

Copy Number Variants and Rare Variants

Copy number variants (CNVs), which are deletions or duplications of genomic regions, have been implicated in the pathogenesis of TS. ^, Studies have identified rare CNVs that are more common in individuals with TS than unaffected controls. These CNVs often encompass genes involved in neurodevelopmental processes, such as synaptic function and neuronal migration. ^,

Next-generation sequencing technologies, including whole-exome and whole-genome sequencing, have enabled the identification of rare single nucleotide variants (SNVs) and small insertion/deletions (indels) that may play a role in TS. ^{, ,} These studies have identified rare, potentially damaging variants in 2 high-confidence TS risk genes, WWC1 (WW and C2 domain containing 1) and CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3) and 4 probable TS risk genes, OPA1 ( OPA1 mitochondrial dynamin like GTPase ), NIPBL ( NIPBL cohesin loading factor ), FN1 ( fibronectin 1 ), and FBN2 ( fibrillin 2 ). Genes identified via rare genetic variants in individuals with TS tend to be instrumental in neurotransmission, synaptic function, cell growth, and organization.

The identification of rare CNVs, SNVs, and indels in TS suggests that the disorder’s genetic architecture may involve a combination of common variants with small effects and rare variants with larger effects. This complex genetic architecture poses challenges to understanding the specific contributions of individual genes to TS risk and highlights the need for larger, well-characterized cohorts and advanced analytical methods.

Shared Genetic Risk with Co-occurring Disorders

TS often co-occurs with other neurodevelopmental and psychiatric disorders, such as ADHD, OCD, and ASD. Only about 10% of TS cases present as “pure” TS, while up to 50% to 60% of patients are also diagnosed with ADHD or OCD. ^, This high rate of co-occurrence suggests that shared genetic risk factors may contribute to the development of these disorders.

Genetic studies have revealed significant overlap in the genetic risk loci and pathways associated with TS and commonly co-occurring disorders. ^{, ,} For example, rare CNVs identified as risk factors for TS have also been implicated in other neurodevelopmental disorders, such as ASD, schizophrenia, and epilepsy. Additionally, variants in genes encoding cell adhesion molecules, such as neurexins and neuroligins, have been repeatedly implicated in the etiology of TS and other neurodevelopmental phenotypes.

GWAS also identified shared genetic risk factors between TS and co-occurring conditions. For instance, a significant proportion of TS polygenic heritability is shared with OCD, ADHD, and migraine. Moreover, a meta-analysis of top loci from GWAS of TS and ADHD reported TBC1D7 (TBC1 domain family member 7) as the top signal, a gene that has also been associated with migraine. ^,

A recent cross-disorder analysis focusing on TS, ADHD, ASD, and OCD confirmed the existence of a unifying genetic factor across TS, ADHD, and ASD, with a separate genetic correlation between TS and OCD. This study identified 13 genomic risk regions that were highly pleiotropic across all disorders analyzed, with the top locus being LINC00461 ( MIR9-2 host gene ), a gene highly expressed in the brain and previously implicated in neurologic diseases. ^,

Identifying shared genetic risk factors between TS and co-occurring disorders has important implications for understanding the biological mechanisms underlying their co-occurrence. These findings suggest that common genetic pathways, such as those involved in neurodevelopment, neurotransmission, and synaptic function, may contribute to the development of multiple related conditions. ^, Understanding these shared genetic risks may inform the development of targeted therapies that address the underlying biological mechanisms common to TS and its comorbidities.

Epigenetics

While genetic factors play a significant role in the development of TS, a proportion of the risk is thought to be influenced by environmental factors and gene-by-environment interactions. This has led to the investigation of epigenetic associations in TS, although studies in this area are currently limited.

One study found that the microRNA, miR-429, was underexpressed in patients with TS compared to controls and may contribute to the regulation of neurodifferentiation and synaptic transmission. Another study, the first epigenome-wide association study of tic disorders, identified 57 DNA methylation sites that were potentially associated with TS, although none reached genome-wide significance. Interestingly, these sites were enriched for brain-specific and developmental processes, and 8 of the top 57 sites mapped to genes previously associated with neuropsychiatric disorders, such as OCD, ASD, bipolar disorder, schizophrenia, and intellectual disability.

While these findings suggest that epigenetic mechanisms may play a role in the development of TS, as they do in other neuropsychiatric disorders, more research is needed to fully understand the impact of epigenetic factors on TS risk and pathogenesis.

In summary, genetic studies have provided strong evidence for shared genetic risk factors between TS and its comorbid disorders, particularly ADHD, OCD, and ASD. These shared risks involve both rare and common genetic variants and implicate biological pathways related to neurodevelopment, neurotransmission, and synaptic function. Epigenetic factors may also contribute to TS risk, although more research is needed in this area. Understanding the complex interplay between genetic and environmental factors in developing TS and co-occurring conditions may lead to identifying new therapeutic targets and personalized treatment approaches.

Clinical Implications

Future Directions and Research Needs