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20 October 2017

Progress in Genetic Studies of Tourette’s Syndrome

,
,
and
1
Laboratoire de Neurogénétique, Centre de Recherche, Institut Universitaire en Santé Mentale de Montréal, Montreal, QC H1N 3V2, Canada
2
Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing 100088, China
3
Center of Schizophrenia, Beijing Institute for Brain Disorders, Beijing 100088, China
4
Département de Psychiatrie, Faculté de Médecine, Université de Montréal, Montreal, QC H3C 3J7, Canada
Brain Sci.2017, 7(10), 134;https://doi.org/10.3390/brainsci7100134
This article belongs to the Special Issue Cerebral Etiology and Treatment of the Gilles de la Tourette Syndrome
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Abstract

Tourette’s Syndrome (TS) is a complex disorder characterized by repetitive, sudden, and involuntary movements or vocalizations, called tics. Tics usually appear in childhood, and their severity varies over time. In addition to frequent tics, people with TS are at risk for associated problems including attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), anxiety, depression, and problems with sleep. TS occurs in most populations and ethnic groups worldwide, and it is more common in males than in females. Previous family and twin studies have shown that the majority of cases of TS are inherited. TS was previously thought to have an autosomal dominant pattern of inheritance. However, several decades of research have shown that this is unlikely the case. Instead TS most likely results from a variety of genetic and environmental factors, not changes in a single gene. In the past decade, there has been a rapid development of innovative genetic technologies and methodologies, as well as significant progresses in genetic studies of psychiatric disorders. In this review, we will briefly summarize previous genetic epidemiological studies of TS and related disorders. We will also review previous genetic studies based on genome-wide linkage analyses and candidate gene association studies to comment on problems of previous methodological and strategic issues. Our main purpose for this review will be to summarize the new genetic discoveries of TS based on novel genetic methods and strategies, such as genome-wide association studies (GWASs), whole exome sequencing (WES) and whole genome sequencing (WGS). We will also compare the new genetic discoveries of TS with other major psychiatric disorders in order to understand the current status of TS genetics and its relationship with other psychiatric disorders.

1. Introduction and Genetic Epidemiology of Tourette’s Syndrome

1.1. Clinical Features of Tourette’s Syndrome

Tourette’s Syndrome (TS) is a complex neuropsychiatric and developmental disorder characterized by repetitive, sudden, involuntary movements and vocalizations, called tics. Vocal tics demonstrated as the involuntary outburst of obscene words, or socially inappropriate and derogatory remarks, called coprolalia, are rare (in about 8% of TS patients) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [1]. TS is the most serious form of a spectrum of tic disorders [1], not only due to its complexity and duration of tic symptoms, but also due to its higher comorbidity, impairment of social function and compromised quality of life [2]. In TS, tics typically start at 4–6 years old; and the severity peaks around 10–12 years old [3]. The course of TS waxes and wanes [4]. Tic symptoms increase during times of stress, anxiety, fatigue and decrease with focused concentration, such as processing fine motor movements [5]. For long-term clinical course, tic symptoms gradually ease during adolescence. Until early adulthood, approximately 75% of patients have a different degree of decreased tic symptoms, including one-third of patients with complete remission; but a quarter of patients continue to have tics in adulthood [3], which has been shown to be correlated with the severity of tics in late childhood [6,7]. Studies have also shown that comorbidities presented at the onset showed a more severe prognosis [6,8,9]. In addition, poor fine-motor skills and smaller caudate volume in childhood were found to be associated with increased adulthood tic severity [10,11]. These may represent different subtypes of TS, and need to be taken into consideration when planning genetic studies to identify the underlying causes.

1.2. Comorbidities of TS

As one of the prominent characteristics compared to other neuropsychiatric disorders, TS is most often associated with other mental and behavioral symptoms and psychiatric diagnoses [12,13], such as obsessions, compulsions, hyperactivity, distractibility, and impulsivity. Studies have shown that 88–92% of TS patients also suffer from one or more comorbidities, such as attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), Non-OCD anxiety disorders, mood disorders, disruptive behavior disorders, pervasive developmental disorders and problems with sleep [12,14,15,16]. A significant subset of children with TS also have fine motor control and visual-motor integration impairment. The most common age for comorbidity occurrence is around 4–10 years old, except for eating disorder and substance use disorder, which usually begin around 15–19 years old [12]. The most common comorbidity of TS is ADHD, ranging from 60–80%; the second common comorbidity is OCD, ranging from 11–80%, other comorbidities are rage attacks (25–75%), depression (13–76%), sleep problems (12–62%), migraine (25%), and learning disabilities (23%) [13]. High frequencies of comorbidities of TS indicate its clinical heterogeneity, as well as heterogeneity and complexity of the underlying etiologies, pathogenic pathways and neural networks.

1.3. Prevalence of TS

Several systematic reviews, in a total of 44 population studies from Europe, East Asia, Middle East, Far East, Oceania and North America, have reported that TS prevalence is between 0.3% and 0.9% in children [17,18,19]. TS has been reported in different cultures across different populations worldwide with similar phenomenology, but with lower prevalence in the Afro-Americans in the USA and the sub-Saharan Black Africans [17]. There were fewer studies on the prevalence of TS in adults. The prevalence of TS in adults was estimated between 0.05% and 0.1% [19,20]. In general, tic disorders are less common in adults than children, which is consistent with partial or complete remission of tic symptoms during and after adolescence. In addition, studies have also shown that TS prevalence is higher in males than females. Male/female ratio is about 3–4:1 [19,21]. The latest study involving 122,884 Canadians suggested that prevalence of TS is 0.33% and 0.07% in youth (12–17 years old) and adults (>18 years old), respectively; and the sex ratio is reported to be 5.31:1 in youth, and 1.93:1 in adults in this study [22]. Schlander et al. also described that the difference of TS prevalence between males and females decreased in adults [23]. Therefore, TS is a typical neurodevelopmental disorder, which is also influenced by sex difference during brain development.

1.4. Heritability of TS

Family studies have shown that the rate of TS in first-degree relatives of TS patients is 10-to-100-fold higher than general population [24]. The similar results (7- to 22-fold increase) were found in first-degree relatives of patients with chronic tic disorders (CTDs) [24]. In family studies, the heritability of tic disorders was estimated to be between 0.25 and 0.77 [20,25]. The results from the latest family study, which included 4826 individuals with TS or CTDs, suggested that the rate of TS or CTD in first-degree relatives was higher (odds ratio, OR: 18.69) than in second-degree relatives (OR: 4.58) and third-degree relatives (OR: 3.07), when compared with unrelated controls (matched on a 1:10 ratio) [25].
There were also family studies regarding the co-heritability of TS and its comorbidities. In a study of 222 affected sibling-pair (ASP) families collected by the Tourette’s Syndrome Association International Consortium on Genetics (TSAICG), TS, OCD, ADHD, and ADHD + OCD were all found highly heritable in this TS-enriched family cohort; and a significant familial correlation was found between TS and OCD, and between OCD and ADHD. However, there was no significant familial correlation between TS and ADHD; whereas they seemed to share significant environmental correlation [26]. Another study of TS and ADHD, not OCD, suggested that TS and ADHD may still have some overlapped genetic factors [27].
Although initially some single large pedigrees of TS suggested autosomal dominant inheritance [28,29,30,31,32], further complex segregation analysis and principal component analysis in extended large pedigrees ascertained through TS probands indicated that the pattern of TS and other related tic disorders was not consistent with simple Mendelian inheritance, even after modelling explanatory variables, such as obsessive compulsive symptomatology [33]. Notably, there seem to be significant phenotypic variability within pedigrees in terms of severity and comorbidity [34].
Twin studies are important and valuable approach to delineate the genetic contribution to genetic disorder like TS. Price and his collages studied 43 pairs of same-sex twins, including 30 pairs of monozygotic (MZ) and 13 pairs of dizygotic (DZ) in 1985 [35]. Concordances rates for TS were 53% for MZ and 8% for DZ. For tics, concordance rates were up to 77% and 23% for MZ and DZ pairs, respectively. The subsequent study on 16 pairs of MZ twins showed the concordance rate were 56% for TS and 94% for tic disorders [36]. In 2007, Bolton et al. investigated a community sample involving 4662 6 years old twin pairs using a two-phase design. The heritability was estimated at 0.50 for tic disorders; and by assessing 854 pairs at the second phase, concordance rate for tic disorders was 0.64 for MZ pairs and 0.33 for DZ pairs [37]. Another study screened a cohort of Swedish 9 and 12 years old for multi-psychiatric diseases, including tic disorders, autism spectrum disorders (ASD), ADHD, OCD etc. [38]; a total of 17,220 twins were recruited. The results suggested that genetic correlations accounted 0.56 of heritability (95% CI: 0.37–0.68), with concordance rate of 0.38 for MZ pairs and 0.11 for DZ pairs for tic disorder. The same study also estimated the heritability by sex, i.e., 0.26 in girls and 0.39 in boys [38]. The tic heritability of adult twins was estimated at 0.33 in another study by Pinto et al. in 2016 [39].
Both family and twin studies have shown that the etiology of TS is at least partially of genetic origin; however, the inheritance is more likely to be complex than simple Mendeian mode. In general, TS and associated comorbidities have much lower heritability compared to other neuropsychiatric disorders, such as ASD (heritability: 0.80), schizophrenia (SCZ) (heritability: 0.81) and bipolar disorder (BPD) (heritability: 0.75) [40]., indicating other factors during development and from the environmental also play some roles in pathogenesis of TS and its comorbidities [37,38,39].

2. Genome-Wide Linkage Studies of TS

Due to the autosomal dominant-like inheritance pattern in some large extended pedigrees with TS and comorbidities, earlier stage of genetic research of TS had focused on genome-wide linkage studies (GWLSs) of TS families, which assess the probability in a given pedigree or pedigrees, where the disease and the genetic marker(s) are cosegregating. Several chromosomal regions were reported as potential candidate loci for TS through GWLSs, including chromosome 3p21–p14 [41], 4q34–q35 [42,43], 5q35.2–q35.3 [43], 6p21 [44], 7q31 [45,46,47], 11q23–24 [48,49,50], 13q31.1 [51], 15q21.1–15q21.3 [52], and 17q25 [43,53]. However, despite the earlier excitement and optimism about gene discovery for TS through GWLS approach, and some chromosomal regions have been implicated in some TS families, no gene or causal mutation of major effect has been discovered for the above-mentioned TS loci, except for the SLITRK1 locus on chromosome 13 [51] and the HDC locus on chromosome 15 [52]. The reasons behind these earlier disappointing gene discovery endeavors through GWLSs may be multiplicative, including phenotypic complexity, such as clinical and genetic heterogeneity of TS and its associated comorbidities, limited sample size, as well as limitation of the previous genetic technologies and statistical methodologies, e.g., the low coverage and resolution of the microsatellite marker panels. Since linkage analysis is based on calculation of recombination events in limited number of generations, it is sensitive to misspecified genetic information, such as individual affection status, allele frequency, mode and parameters about inheritance. Nevertheless, limited significant statistical results of TS GWLSs strongly suggest that the underlying genetic architecture of TS and associated comorbidities is more complex than simple Mendelian inheritances.

3. Candidate Gene Association Studies of TS

After unsuccessful GWLS attempts in TS gene discovery, researchers had turned to direct candidate gene linkage and association studies to identify the potential genetic contribution of TS. Based on progresses in neuroimaging, postmortem, animal models and pharmacological studies, it has been hypothesized that the cortico-striatal-thalamo-cortical (CSTC) pathways may underlay the pathogenesis of TS and related symptomatology; and abnormalities of those neurotransmitters and their signal transmissions could lead to the dysfunction of CSTC neural network and subsequent clinical manifestation of TS. Multiple neurotransmitter systems have been implicated in CSTC pathways [54], including dopaminergic, serotonergic, glutamatergic, gamma-amino butyric acid-(GABAergic), histaminergic, and other neurotransmitters [55,56,57]. Furthermore, a neurotransmitter dysfunction may also cause change in other neurotransmitters due to interaction or self-regulation among them [57].
Compared to genetic linkage analysis, genetic association is when one or more genotypes within a population, i.e., unrelated cases and controls, co-occur with a phenotypic trait more often than would be expected by chance occurrence. In earlier stage of genetic research of TS, many studies have been carried out to test genetic linkage and associations between various neurotransmitters and TS. Table 1 is a summary of candidate gene linkage and association studies of TS. In general, none candidate gene showed positive linkage result. Some association studies of TS showed positive results; however, their effects in TS seemed to be very small; and very often results were non-replicable; sometimes even controversial. As shown in Table 1, most studies were limited by sample sizes, therefore under power according to current standards. Interestingly, since 2005, majority of genetic association studies have achieved positive results, accounting for bigger sample size, more advanced technical methods and selected genes.
Table 1. Main findings of linkage and association studies of neurotransmitter genes in Tourette’s Syndrome (TS).

4. Genome-Wide Association Studies of TS and Other Psychiatric Disorders

Facilitated by the advent of SNP array technologies and statistical methodologies, as well as the collective efforts of large scale biobanks for research materials, genome-wide association study (GWAS) has become the main stream of genetic studies of common diseases in the past decade. The current GWAS Catalog contains 3055 publications and reports 39,360 unique SNP-trait associations in nearly 2000 traits or diseases [95]. Psychiatric disorders fall into the complex trait category; and most psychiatric disorders are common and highly heritable. Therefore, GWAS has been the focus of considerable effort in field of psychiatric genetics in the past decade. To date, over 400 GWAS studies have been published in psychiatric disorders like SCZ (104 GWAS analyses) [95,96,97], ASD (23 GWAS analyses) [95,98,99], BPD (85 GWAS analyses) [95,100,101], MDD (major depressive disorder) (55 GWAS analyses) [95,102,103], OCD (5 GWAS analyses) [95,104,105] and ADHD (33 GWAS analyses) [95,106,107]. These research results have markedly increased our understanding and knowledge of the genetic basis of these psychiatric disorders, and have yielded empirical data on genetic architecture and pathways critical to address the long-standing debates in the field of psychiatry. Table 2 shows a summary of GWASs of several main psychiatric disorders. In general, the effects of risk variants from GWASs are small but wide-spread genome-wide; and the majority of GWAS-identified variants fall in noncoding regions of the human genome. However, further annotations indicate that these regions are enriched for active elements for gene expression regulation in relevant cell functions [108,109].
Table 2. Genome-wide association studies (GWAS) findings in main psychiatric disorders.
So far, only two GWASs of TS and one replication study have been published to date; one reached a marginal genomewide significance and the other GWAS failed to identify genome-wide significant loci for TS [110,111,112]. These results may have a close relationship with the sample size (1285 cases/4964 controls, and 2498 cases/6277 controls, respectively for each TS GWAS), which were much smaller than other major psychiatric GWASs. To date, there are no significant finding in ADHD and OCD GWASs either, most likely due to limited sample sizes as well. Nevertheless GWASs of ADHD and OCD found some top signals within some interesting candidate genes, such as LMOD2, WASL, ASB15, and SHFM1 genes in ADHD GWASs [113,114]; and PTPRD [104] and FAIM2 [105] genes in OCD GWASs.
One unambiguous conclusion from all GWASs is that complex traits are polygenic; and multiple lines of evidence are consistent with widespread pleiotropy for complex traits; these features are particularly striking in GWASs of psychiatric disorders. Widespread but small effects indicate that these common risk variants are not the main cause of disease phenotype under study, but rather just reflect the minimal peripheral polymorphic effects of the underlying molecular networks in different individuals and populations; and in case of TS GWAS, the subtle functional diversity or polymorphisms of the CSTC network.

5. Chromosomal Abnormalities and Copy Number Variants (CNVs) of TS

Chromosomal aberrations studies are an important aspect of TS genetics with more significant findings. By single or combined in situ hybridization, chromosomal microarray, cytogenetic and next-generation sequencing, chromosomal aberrations studies have identified several large, rare structural aberrations associated with TS and related phenotypes. Table 3 is a summary of some main candidate loci and genetic findings. Among the most interesting candidate genes, Slit and Trk-like, family member 1 (SLITRK1) gene on 13q31.1, discovered in a TS patient with a de novo inversion [51]. SLITRK1 is a transmembrane protein that regulates neurite outgrowth by phosphorylation-dependent manner; and it has been shown to control neurite outgrowth; and it is expressed in the embryonic and postnatal brain, including the cortex, thalamus, and basal ganglia, which correlate with the neuroanatomical regions most commonly implicated in TS [119,120,121]. Inner mitochondrial membrane protein 2L (IMMP2L) gene on 7q22–q31 is also an interesting candidate gene for TS, disrupted by a breakpoint in 7q31 in TS patients, as well as implicated in autism and speech-language disorders [45,46,122,123]. IMMP2L encodes the inner membrane peptidase subunit 2, a mitochondrial protease involved in cleaving the space-sorting signals of mitochondrial membrane proteins; and defective IMMP2L may lead to disrupted mitochondria function [123]. Mitochondrial dysfunction has been associated with a range of human disorders, including neuropsychiatric disorders [123]. Disruptions of Contactin associated protein-like 2 gene (CNTNAP2) on 7q35–q36 [124,125] and Neuroligin 4 (NLGN4) on Xp22.3 [126] have also been reported to be associated with TS and other neurodevelopmental disorders.
Table 3. Genomic structural aberrations in TS.
CNV is a special type of structural variation, i.e., a type of duplication or deletion event that affects a considerable number of base pairs at the same chromosomal location [142]. CNVs have been identified as causal genetic variants in other psychiatric disorders [143,144]. It has been reported that de novo CNVs are strongly associated with ASD and SCZ [143,144,145,146,147,148,149]. In ASD, de novo CNV in simplex families is 5 times and 10 times higher than multiplex families and controls, respectively [145]. In SCZ, de novo CNV is 8 times higher in sporadic cases than in controls [148]. It has been estimated that increased large CNV and chromosomal rearrangement may contribute to 5–10% risk of ASD [149]. The other neurodevelopmental conditions, such as bipolar disorder, epilepsy, and intellectual deficiency also share a highly similar large CNV landscape with potential pathogenicity [150,151].
Table 4 summarizes CNV studies in TS. Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS structural variants, as well as increased global CNV burden that is mainly driven by large, rare, clinically relevant events, contribute significantly to the genetic architecture of TS, in which larger CNVs could create imbalance for more genes during neurodevelopment and lead to more severe outcomes.
Table 4. Copy number variations in TS.

6. Whole Exome/Genome Sequencing Studies of TS and Other Psychiatric Disorders

Whole exome sequencing (WES) is a fast and cost-effective method by sequencing all coding regions of the entire human genome to detect rare deleterious variants, which disrupt encoded protein function. Whole genome sequencing (WGS) is to sequence the entire genome, including intron, exon, flanking sequence and interval regions. Unlike GWASs that identify common variants (frequency ≥ 5%), WES/WGS are used to identify rare (frequency ≤ 1%) and novel variants genome-wide. WES has achieved great success in Mendelian disorders [157]; but also used as an effective means to identify loci for complex traits or diseases [158]; and these protein-coding regions contain 85% of disease-causative mutations, even if they only cover less than 2% of the entire genome [159,160,161]. Coming after WES, WGS allows to identify private genetic variants, small insertions and deletions (indels), more complex CNVs, and other structural alterations; and most of these variants reside in the ~98% noncoding genome largely unexplored by SNP microarray and WES studies. With the application of WES/WGS, some rare mutations including de novo point mutations, gene-disrupting structural mutations have been found in psychiatric disorders [162,163,164,165], in which loss of functional variants (nonsense, splice-site variants), and increased burden of de novo mutations, have been shown to play an important role in etiology of psychiatric disorders [165].
Some major studies and findings of WES and WGS in psychiatric disorders are summarized in Table 5. So far, the application of WES has generated the most significant results in ASD than in any other psychiatric disorders, and multiple large scale studies have identified numerous candidate genes for ASD [166,170,171,174,186,187,188,189,190,191,192,193,194,195]. Compared to WES, WGS studies are much newer and with fewer number of studies and with smaller sample sizes for current studies. However, with reduced cost and improved methodologies, the application of WGS has been rapidly increased in genetic studies of complex disorders [179,180,181,196,197,198]. WES/WGS studies have further demonstrated that psychiatric disorders like SCZ, BPD, ASD belong to complex traits, rather than monogenetic disorders; and the underlying pathogenic mechanisms and pathways are perplexing. There are fewer studies of WES/WGS in TS. Sundaram et al. performed WES in ten members of one pedigree with seven affected by TS; and identified three novel nonsynonymous variants within MRPL3, DNAJC13 and OFCC1 genes [199]. Willsey et al. performed WES in two TS cohorts (325 trios from the Tourette International Collaborative Genetics cohort; 186 trios from the Tourette Syndrome Association International Consortium on Genetics), and suggested that de novo damaging variants found in approximately 400 genes may contribute to genetic risk in 12% of clinical cases of TS; and they particularly reported 4 likely risk genes for TS, i.e., WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1) [200]. Eriguchi et al. identified 30 de novo mutations, including four missense mutations (RICTOR, STRIP2, NEK10, and TNRC6A genes) in WES of nine trio families and one quartet family of TS [201]. Sun et al. identified a nonsense mutation through WES in the PNKD gene segregating with TS and Tic disorders in six out of nine members in a three-generation TD multiplex family [202]. These five above-mentioned candidate genes are enriched in CSTC regions, which are implicated TS; and their expression levels vary in different development stages, suggesting that disruptive protein function of those genes might affect neuronal development or activity in these brain structures [201,202]. Compared to ASD, SCZ and MDD, WES/WGS in TS are limited by the small sample sizes [199,200,201,202]. Further studies with enlarged sample size will be helpful to understand the genetic architecture of TS and its overlap with other neuropsychiatric disorders.
Table 5. Main whole exome sequencing/whole genome sequencing (WES/WGS) findings in major psychiatric disorders.

7. Epigenetics and TS

Decades of genetic research have shown that there are no direct correlations between genotypes and phenotypes in psychiatric disorders; and there ought to be missing pieces of information between genomic variations and disease phenotypes, i.e., changes of genomes will only become effective through transcsriptome, epigenome and result in phenotypic outcomes. Epigenetics refers to the ongoing regulation of gene expression, which includes structural modification of chromatin, post-translational modification of histones (i.e., acetylation and methylation), chemical modification of DNA through methylation or hydroxymethylation of cysteins, as well as expression of interfering non-coding RNAs (i.e., miRNAs and long-non-coding RNAs) [203,204]. These epigenetic mechanisms allow reprogramming of the genome upon environmental inputs at specific time-points during development and through lifetime. The epigenetic changes triggered by early life events stand as a valuable hypothesis of the environmentally induced behavioral changes.
Epigenetic regulation has been shown to have an impact on the development of many neuropsychiatric disorders [205,206], and to play a pivotal role in embryonic and adult neurogenesis [207]. Some studies on epigenetic processes in the expression and inheritance of behaviors have helped us to further understand the complexity of brain functions [208]. Abelson et al. identified a noncoding RNA variant (var321) at the binding site for microRNA hsa-miR-189 in two unrelated TS patients on chromosomal 13 [51] (see above). In 2015, Rizzo et al. found that miR-429 was significantly underexpressed in TS patients and suggested as an useful molecular biomarker to aid TS diagnosis in the future [209]. Another study suggested that methylation levels of the DRD2 gene were higher in adults with TS than in sex-, age-matched controls [210]; and methylation of DRD2 was positively correlated with tic severity. However, methylation of DAT was negatively correlated with tic severity in the same study [210]. State et al. reported that there might be relationship between chromosome 18(q21–q22) inversion and epigenetic mechanism in a 12 year old boy with TS and OCD [140]. The results from the first epigenome-wide association study, which investigated DNA methylation in patients with tic disorders, suggested that the top hits of methylation signal were enriched for genes involved in brain-specific and developmental processes [211]. Delgado et al. did not find significant methylation difference in TS patients compared with controls in a region of chromosome 8 for KCNK9 and TRAPPC9 genes [212].

8. Conclusions

TS is a complex disorder with highly variable phenotypic manifestations and high frequency of comorbidities. It is more common in males than in females. Family and twin studies have shown that genetic factors play an important role in the pathogenesis of TS. Candidate genes studies have shown that multiple genes (DRD2, DRD4, 5-HT2C, SERT) in multiple neural systems, including dopaminergic, serotonergic, histaminergic pathways, might be associated with pathogenesis of TS, but results are not yet convincing enough. In recent years, several new candidate genes, e.g., SLITRK1, IMMP2L, CNTNAP2, NLGN4, have been identified through linkage studies and structural genomic aberrations, in which very rare genetic variants with large effects were found in TS patients and families.
Compared to genetic studies of other psychiatric disorders, TS studies are currently still largely limited by the relatively small sample sizes, because of the complexity and heterogeneity in clinical manifestation. We expect that more rare and common variants with various effects underlying the genetic susceptibility of TS will be discovered through larger-scale international collaborative projects in the near future. Combinational analyses of common variants with rare variants, structural variations and CNVs, plus epigenetic factors; i.e., integrative “multi-omics” together with environmental factor analyses [213,214] will be the future direction. As promising starts, four large collaborative groups with joint effort and multiple resources have been developed for TS genetic research, focusing on existing large well-characterized patient cohorts, which include (1) the Tourette Syndrome Association International Consortium for Genetics (TSAICG) [215]—genomewide association studies for TS; (2) the Tourette international collaborative genetics (TIC genetics) study—whole exome sequencing in families with TS [216], which is funded by the National Institute of Mental Health (NIMH) in the USA; (3) the European multicentre tics in children (EMTICS) study—exploring gene-environment interactions that underlie TS etiology, which is funded by the European Commission under the Seventh Framework Programme, including 17 clinical sites from across Europe [217]; (4) TS-EUROTRAIN—coordinating large-scale studies and training the next generation of experts for TS, supported by the European Commission [218,219]; (5) Of particular interest in this field, the PsychENCODE project has been created and developed by an international consortium to provide an enhanced framework of regulatory genomic elements (promoters, enhancers, silencers and insulators), catalog epigenetic modifications and quantify coding and non-coding RNA and protein expression in tissue and cell-type-specific samples from healthy (neurotypical) control and disease-affected post-mortem human brains, as well as functionally characterize disease-associated regulatory elements and variants in model systems. [220]. The Project is currently focusing on three major psychiatric disorders: ASD, BPD and SCZ, for example, 98 of the 108 independently associated loci were found in non-coding region in SCZ GWAS [96,221] suggesting that the PsychENCODE project will be a valuable platform to study the epigenetics of psychiatric disorders in the future, including TS studies, in which some preliminary results indicated that epigenetics might play a role in TS as well [51,140,209,210,211].
In the near future, GWAS by SNP arrays will most likely be gradually replaced by WGS, with increased power by including rare variants in the genetic analyses. For many years, genotyping technology was the limiting step to genetic discoveries, but now discovery is limited by phenotypic descriptors that could link with genetic data to allow disease stratification, which might be more aligned with treatments; therefore, deep phenotyping aligned with genetic studies will also facilitate new discoveries for disease risk and mechanism.
Although with limited results, epigenetic research has shown promising hope to link the genomic variations with environmental exposures and disease outcomes, particularly for psychiatric disorders and behavioral phenotypes. For TS, further studies with larger sample size could focus on further understanding of the effect of dynamic epigenome on the regulation of developmental genes and behaviors. Additional large-scale studies could also aim to disentangle common versus disorder-specific genomic and epigenomic variations in TS with other psychiatric and behavioral phenotypes. Understanding the mechanism behind the sex differences in TS may also help us better understand the regulation of gene expression in the brain and its implication in TS pathogenesis because TS is a male-biased disease.

Acknowledgments

Yanjie Qi would like to thank the fellowship provided by the Beijing Anding Hospital for her study in Montreal, Canada. The co-authors would like to thank the editors and reviewers for their support and help for this manuscript.

Author Contributions

Y.Q. and L.X. planned and drafted the manuscript; L.X. revised and finalized; Y.Z. and Z.L. advised and commented on the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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