Development and Validation of an Assessment-Driven Behavioral Intervention for Primary Complex Motor Stereotypies in Young Children.

Complex motor stereotypies are rhythmic, repetitive, fixed, and non-goal directed movements (e.g., bilateral flapping/waving movements of the hands/arms). Movements typically begin in early childhood and can occur in otherwise normally developing ("primary") or autistic ("secondary") children. Stereotypies persist, occur multiple times a day, have prolonged durations, can be socially stigmatizing, and may lead to bullying and isolation. Prior behavioral treatment studies have focused on older children (ages 6-12) and report modest reductions in stereotypy (i.e., between 14% and 33%). The current study involves the functional assessment and treatment of five children with Primary Complex Motor Stereotypy using a modified awareness training procedure, differential reinforcement of other behavior, and schedule thinning in a nonconcurrent multiple baseline design. Results suggest a 99% reduction of motor stereotypy from baseline across all participants.

The Challenge of Examining Social Determinants of Health in People Living With Tourette Syndrome.

BACKGROUND: To examine the association between race, ethnicity, and parental educational attainment on tic-related outcomes among Tourette Syndrome (TS) participants in the Tourette Association of America International Consortium for Genetics (TAAICG) database. METHODS: 723 participants in the TAAICG dataset aged ≤21 years were included. The relationships between tic-related outcomes and race and ethnicity were examined using linear and logistic regressions. Parametric and nonparametric tests were performed to examine the association between parental educational attainment and tic-related outcomes. RESULTS: Race and ethnicity were collapsed as non-Hispanic white (N=566, 88.0%) versus Other (N=77, 12.0%). Tic symptom onset was earlier by 1.1 years (P < 0.0001) and TS diagnosis age was earlier by 0.9 years (P = 0.0045) in the Other group (versus non-Hispanic white). Sex and parental education as covariates did not contribute to the differences observed in TS diagnosis age. There were no significant group differences observed across the tic-related outcomes in parental education variable. CONCLUSIONS: Our study was limited by the low number of nonwhite or Hispanic individuals in the cohort. Racial and ethnic minoritized groups experienced an earlier age of TS diagnosis than non-Hispanic white individuals. Tic severity did not differ between the two groups, and parental educational attainment did not affect tic-related outcomes. There remain significant disparities and gaps in knowledge regarding TS and associated comorbid conditions. Our study suggests the need for more proactive steps to engage individuals with tic disorders from all racial and ethnic minoritized groups to participate in research studies.

Sex Differences in People with Tourette Syndrome and Persistent Motor or Vocal Tic Disorder in the Tourette Association of America International Consortium for Genetics Database.

Background and Objective: Tourette Syndrome (TS) and Persistent Motor or Vocal Tic Disorders (PMVT) are more prevalent in males (vs. females). Females with TS may have a delay in diagnosis, and more complex tic features (vs. males). With respect to comorbidities, obsessive-compulsive disorder (OCD) is more prevalent in females; attention-deficit hyperactivity disorder (ADHD) is more prevalent in males. Less is known about sex differences in PMVT. This study analyzes sex differences in outcomes among individuals with TS and PMVT in the Tourette Association of America International Consortium for Genetics dataset (TAAICG). Design/Methods: Data from 2403 individuals (N=2109 TS; N=294 PMVT) from the TAAICG were analyzed to explore the relationship between sex and TS or PMVT outcomes: age at tic onset; age at diagnosis; time-to-diagnosis; tic severity; and comorbidity rates. Regression models were adjusted for age and family relationships to examine the impact of sex on outcomes. Results: Females with TS (25.5% of the sample) had a later age of symptom onset (6.5±2.8 vs. 6.0±2.7; p=0.001), later age at diagnosis (13.3±11.2 vs. 10.7±8.1; p=0.0001), and a longer time-to-diagnosis [3 (1,7) vs. 2 (1,5), p=0.01] than males. The total Yale-Global Tic Severity Scale (YGTSS) was lower in females with TS (28.4±9.1 vs. 30.7±8.7); p<0.0001); OCD was slightly more prevalent in females (55% vs. 48.7%; p=0.01) although OCD severity did not differ by sex; ADHD was more prevalent in males (55.7% vs 38.9%; p<0.001). Females with TS had 0.46 lower odds of being diagnosed with TS (p<0.00001). Females with PMVT (42.9% of the sample) had an earlier age of symptom onset (7.9±3.3 vs. 8.9±3.7; p=0.05). Motor or vocal tic severity (YGTSS) was not significantly different. OCD, but not ADHD, was more prevalent in females (OCD: 41.9% vs. 22.2%; p<0.001: ADHD:16.5% vs 21.0%; p=0.4). Conclusion: Females with TS are less likely to be formally diagnosed and have a later age of symptom onset, later age at diagnosis, longer time-to-diagnosis, higher prevalence of OCD, and lower prevalence of ADHD (vs. males). Females with PMVT have an earlier age of symptom onset, higher prevalence of OCD, but similar ADHD prevalence rates (vs. males). Females with TS and PMVT may be clinically different than males with TS. Future research is needed to understand differences longitudinally in TS and PMVT.

Primary complex motor stereotypies are associated with de novo damaging DNA coding mutations that identify KDM5B as a risk gene.

Motor stereotypies are common in children with autism spectrum disorder (ASD), intellectual disability, or sensory deprivation, as well as in typically developing children ("primary" stereotypies, pCMS). The precise pathophysiological mechanism for motor stereotypies is unknown, although genetic etiologies have been suggested. In this study, we perform whole-exome DNA sequencing in 129 parent-child trios with pCMS and 853 control trios (118 cases and 750 controls after quality control). We report an increased rate of de novo predicted-damaging DNA coding variants in pCMS versus controls, identifying KDM5B as a high-confidence risk gene and estimating 184 genes conferring risk. Genes harboring de novo damaging variants in pCMS probands show significant overlap with those in Tourette syndrome, ASD, and those in ASD probands with high versus low stereotypy scores. An exploratory analysis of these pCMS gene expression patterns finds clustering within the cortex and striatum during early mid-fetal development. Exploratory gene ontology and network analyses highlight functional convergence in calcium ion transport, demethylation, cell signaling, cell cycle and development. Continued sequencing of pCMS trios will identify additional risk genes and provide greater insights into biological mechanisms of stereotypies across diagnostic boundaries.

Creating a Patient-Based Diagnostic Checklist for Functional Tics During the COVID-19 Pandemic.

Background and Objectives: Since the onset of the COVID-19 pandemic, there has been a dramatic change in the presentation of patients with tics. The explosive presentation of atypical tics (TT) has been noted worldwide and thought to be the manifestation of a pandemic-associated functional neurologic disorder following social media exposure to tics. Nevertheless, despite the frequent diagnosis of functional tics (FT), there are no existing formal diagnostic criteria. The primary aim of this study was to create a patient-based diagnostic checklist for making the diagnosis of a functional tic disorder (FTD) during the COVID-19 pandemic. Methods: A retrospective chart review at a single institution during the pandemic was performed. Based on the available literature, diagnostic criteria were created for TT, FT, and patients with dramatically evolving symptoms (i.e., mixed with prior history of mild tics with later fulminant functional worsening). Patient demographics, comorbidities, and tic characteristics of these groups were then compared. Following initial assessments, new diagnostic criteria were established and statistically reanalyzed. Results: One hundred ninety-eight patients underwent investigation. Significant differences in age, sex, psychological comorbidities, tic characteristics, and tic severity were found between patients with TT when compared with either of the 2 the functional groups. Only the presence of rostrocaudal progression and increased obsessive-compulsive behaviors were significantly different between patients with new-onset FT and those with functional worsening of a previous tic disorder. Results also showed that age at tic onset was not a contributing factor for group differentiation. Many patients with FT were not exposed to videos depicting tics on social media. Discussion: This study confirms the presence of a distinct presentation of aTT during the pandemic period. It further establishes the validity of specific criteria useful in dividing patients with tics into 3 formal diagnostic criteria: (1) primary tic disorders (PTDs), (2) a strictly FTD, and (3) a mixed tic disorder consisting of patients with an initial history of a PTD and the later development of FT. Explicit diagnostic criteria should enable clinicians and researchers to make a definitive identification and assist patients and families become more knowledgeable and accepting of the diagnosis of FT.

Pandemic intake questionnaire to improve quality, effectiveness, and efficiency of outpatient neurologic and developmental care at the Kennedy Krieger institute during the COVID-19 pandemic.

Background: The COVID-19 pandemic uniquely affects patients with neurologic and developmental disabilities at the Kennedy Krieger Institute. These patients are at increased risk of co-morbidities, increasing their risk of contracting COVID-19. Disruptions in their home and school routines, and restrictions accessing crucial healthcare services has had a significant impact. Methods: A Pandemic Intake questionnaire regarding COVID-19 related medical concerns of guardians of patients was distributed using Qualtrics. Data from May-December 2020 were merged with demographic information of patients from 10 clinics (Center for Autism and Related Disorders (CARD), Neurology, Epigenetics, Neurogenetics, Center for Development and Learning (CDL) Sickle Cell, Spinal Cord, Sturge-Weber syndrome (SWS), Tourette's, and Metabolism). A provider feedback survey was distributed to program directors to assess the effectiveness of this intervention. Results: Analysis included responses from 1643 guardians of pediatric patients (mean age 9.5 years, range 0-21.6 years). Guardians of patients in more medically complicated clinics reported perceived increased risk of COVID-19 (p < 0.001) and inability to obtain therapies (p < 0.001) and surgeries (p < 0.001). Guardian responses from CARD had increased reports of worsening behavior (p = 0.01). Providers increased availability of in-person and virtual therapies and visits and made referrals for additional care to address this. In a survey of medical providers, five out of six program directors who received the responses to this survey found this questionnaire helpful in caring for their patients. Conclusion: This quality improvement project successfully implemented a pre-visit questionnaire to quickly assess areas of impact of COVID-19 on patients with neurodevelopmental disorders. During the pandemic, results identified several major areas of impact, including patient populations at increased risk for behavioral changes, sleep and/or disruptions of medical care. Most program directors reported improved patient care as a result.

The Role of the Cerebellum in Repetitive Behavior Across Species: Childhood Stereotypies and Deer Mice.

Recent studies suggest that the cerebellum may have a significant role in repetitive behaviors. In primary complex motor stereotypies, typically developing children have repetitive movements usually involving rhythmic flapping/waving arm/hand movements. Similarly, the deer mouse animal model exhibits inherited repetitive behaviors, with increased frequencies of spontaneous jumping and rearing. In this study, data from both children with motor stereotypies and deer mice were used to investigate the role of the cerebellum in repetitive behaviors. The 3.0-T MRI volumetric imaging of the cerebellum was obtained in 20 children with primary complex motor stereotypies and 20 healthy controls. In deer mice, cerebellar volume (n = 7/group) and cell counts (n = 9/group) were compared between high- and low-activity animals. Levels of cerebellar neurotransmitters were also determined via HPLC (n = 10/group). In children with stereotypies, (a) there were a statistically significant reduction (compared to controls) in the white matter volume of the posterior cerebellar lobule VI-VII that negatively correlated with motor control and (b) an 8% increase in the anterior vermis gray matter that positively correlated with motor Stereotypy Severity Scores (SSS). In deer mice, (a) there was a significant increase in the volume of the anterior vermal granular cell layer that was associated with higher activity and (b) dentate nucleus cell counts were higher in high activity animals. Similar increases in volume were observed in anterior vermis in children with stereotypies and a deer mouse model of repetitive behaviors. These preliminary findings support the need for further investigation of the cerebellum in repetitive behaviors.

Frequency and Intensity of Premonitory Urges-to-Tic in Tourette Syndrome Is Associated With Supplementary Motor Area GABA+ Levels.

BACKGROUND: Individuals with Tourette syndrome (TS) often report that they express tics as a means of alleviating the experience of unpleasant sensations. These sensations are perceived as an urge to act and are referred to as premonitory urges. Premonitory urges have been the focus of recent efforts to develop interventions to reduce tic expression in those with TS. OBJECTIVE: The aim of this study was to examine the contribution of brain γ-aminobutyric acid (GABA) and glutamate levels of the right primary sensorimotor cortex (SM1), supplementary motor area (SMA), and insular cortex (insula) to tic and urge severity in children with TS. METHODS: Edited magnetic resonance spectroscopy was used to assess GABA+ (GABA + macromolecules) and Glx (glutamate + glutamine) of the right SM1, SMA, and insula in 68 children with TS (MAge = 10.59, SDAge = 1.33) and 41 typically developing control subjects (MAge = 10.26, SDAge = 2.21). We first compared GABA+ and Glx levels of these brain regions between groups. We then explored the association between regional GABA+ and Glx levels with urge and tic severity. RESULTS: GABA+ and Glx of the right SM1, SMA, and insula were comparable between the children with TS and typically developing control subjects. In children with TS, lower levels of SMA GABA+ were associated with more severe and more frequent premonitory urges. Neither GABA+ nor Glx levels were associated with tic severity. CONCLUSIONS: These results broadly support the role of GABAergic neurotransmission within the SMA in the experience of premonitory urges in children with TS. © 2021 International Parkinson and Movement Disorder Society.

Clinical Practice Patterns in Tic Disorders Among Movement Disorder Society Members.

Background: Tic disorders belong to the broad spectrum of pediatric and adult movement disorders. The wide variability in clinical presentations, applied assessment tools, and treatments are poorly understood. Objectives: To map practices and knowledge base of movement disorder clinicians concerning clinical features, pathophysiology, and treatment approaches in tic disorders. Methods: A 33-item survey was developed by the Tic Disorders and Tourette syndrome Study Group members of the Movement Disorder Society. The survey was distributed to the complete society membership and included responses from 346 members, 314 of whom reported treating tic disorders. Results: Approximately one third of survey respondents (35%) frequently evaluated patients with tics. The data revealed widespread use of existing guidelines (about 70%) and screening for comorbid disorders (>90%). The most common investigations used to rule out secondary causes of tics were imaging (92%), laboratory tests (66%) and neurophysiology (38%). Functional tics were the second most common tic etiology following primary tics. Only 27% of respondents reported confidence in knowledge about tic pathogenesis. Top rated interventions to treat tics were psychoeducation, cognitive behavioral intervention for tics (CBIT) and treatment for neuropsychiatric comorbidities. Antipsychotics were ranked as the most effective pharmacologic tic intervention. Conclusions: The majority of movement disorders specialists do not frequently encounter tics. There was sparse knowledge about tic pathophysiology. Psychoeducation, CBIT, the treatment of neuropsychiatric comorbidities and use of antipsychotics emerged as the most common interventions to treat tics. These results provide insight into what will be needed to improve the diagnosis and treatment of tic disorders.

Aberrant prefrontal cortical-striatal functional connectivity in children with primary complex motor stereotypies.

Motor stereotypies are rhythmic, repetitive, prolonged, predictable, and purposeless movements that stop with distraction. Although once believed to occur only in children with neurodevelopmental disorders such as autism, the presence and persistence of complex motor stereotypies (CMS) in otherwise typically developing children (primary CMS) has been well-established. Little, however, is known about the underlying pathophysiology of these unwanted actions. The aim of the present study was to use resting-state functional magnetic resonance imaging to evaluate functional connectivity within frontal-striatal circuits that are essential for goal-directed and habitual activity in children with primary complex motor stereotypies. Functional connectivity between prefrontal cortical and striatal regions, considered essential for developing goal-directed behaviors, was reduced in children with primary CMS compared to their typically developing peers. In contrast, functional connectivity between motor/premotor and striatal regions, critical for developing and regulating habitual behaviors, did not differ between groups. This documented alteration of prefrontal to striatal connectivity could provide the underlying mechanism for the presence and persistence of complex motor stereotypies in otherwise developmentally normal children.

Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.

Efficacy of Parent-Delivered, Home-Based Therapy for Tics.

BACKGROUND: Although behavioral therapy is an effective approach to reduce tics in children and adults, there is an insufficient availability and accessibility of behavioral therapy in the community. OBJECTIVE: The goal of the study was to test the clinical efficacy of home-based, parent-provided behavioral therapy in children with Tourette syndrome aged seven to 13 years. METHOD: An instructional habit reversal training-based video and guide was developed for use by parents. Eligible families, in this 10-week study, were enrolled in either a home-based therapy (DVD) group (received disk and written instructions) or an in-person therapist group (had scheduled visits with the therapist). Outcome scales included the Yale Global Tic Severity Scale, both the total Tic Severity Score and total Global Severity Score, and the parent report of Clinical Global Impressions of Improvement. RESULTS: Forty-four children (mean age = 10.21 ± 1.69 years) were enrolled into either the DVD (n = 33) or in-person therapist (n = 11) groups. Eighteen completed the study-eight in the DVD and 10 in the in-person therapist group. Outcome measures showed significant reductions in Yale Global Tic Severity Scale change ratios: mean improvement on the Tic Severity Score was DVD 32.4% (P < 0.001) and in-person therapist 26.6% (P = 0.01); and for the Global Severity Score, DVD 33.7% (P < 0.001) and in-person therapist 26.7% (P < 0.001). CONCLUSIONS: Home-based, parent-administered habit reversal training behavioral therapy is efficacious for reducing tics in children. Telephone contacts early in the DVD treatment course might reduce the number of dropouts.

Cortical endogenous opioids and their role in facilitating repetitive behaviors in deer mice.

Deer mice provide a non-pharmacologically induced model for the study of repetitive behaviors. In captivity, these animals develop frequent jumping and rearing that resemble clinical symptoms of obsessive-compulsive behavior (OCB), autism spectrum disorder (ASD), complex motor stereotypies (CMS), and Tourette's syndrome (TS). In this study, we pursue the mechanism of repetitive behaviors by performing stereological analyses and liquid chromatography/ mass spectrometry (LC-MS/MS) measurements of glutamate (Glut), GABA, 3,4-dihydroxyphenylacetic acid (DOPAC), dopamine (DA), leu-enkephalin (leu-enk), and dynorphin-A (dyn-A) in frontal cortex (FC), prefrontal cortex (PFC), and basal ganglia. The only significant stereological alteration was a negative correlation between repetitive behaviors and the cell count in the ventromedial striatum (VMS). Neurochemical analyses demonstrated a significant negative correlation between repetitive behaviors and endogenous opioids (leu-enk and dyn-A) in the FC - the site of origin of habitual behaviors and cortical projections to striatal MSNs participating in direct and indirect pathways. The precise neurochemical process by which endogenous opioids influence synaptic neurotransmission is unknown. One postulated cortical mechanism, supported by our findings, is an opioid effect on cortical interneuron GABA release and a consequent effect on glutamatergic cortical pyramidal cells. Anatomical changes in the VMS could have a role in repetitive behaviors, recognizing that this region influences goal-directed and habitual behaviors.

Evidence-based treatment of Tourette's disorder and chronic tic disorders.

Introduction: Chronic Tic Disorders and Tourette's Disorder (collectively referred to as TD) are characterized by sudden, rapid, and repetitive motor movements or vocalizations called tics. Children, adolescents, and adults with TD often experience co-occurring psychiatric symptoms and impairments in multiple domains. As a result of tics and other symptoms, patients with TD can develop negative self-views, require considerable accommodations, and experience a poor quality of life. Therefore, the efficient and effective management of TD bears considerable importance. Areas covered: This expert review evaluated the empirical support for behavioral and pharmacological interventions based on the results of randomized controlled trials (RCTs). Behavioral interventions evaluated include habit reversal training (HRT), comprehensive behavioral intervention for tics (CBIT), and exposure response prevention (ERP). Reviewed pharmacological interventions included alpha-2 agonists, antipsychotics, and anticonvulsants. Expert opinion: This review identified several efficacious behavioral and pharmacological interventions for TD. However, several gaps in the management of TD include: (1) the access/availability of behavioral interventions, (2) novel and more efficacious treatment approaches, and (3) the development of more comprehensive interventions to manage TD. In order to advance the treatment of TD, additional research is necessary to efficiently, effectively, and comprehensively develop and evaluate new treatments for patients with TD.

Controversies Surrounding the Pathophysiology of Tics.

Tics are sudden, rapid, recurrent, nonrhythmic motor movements or vocalizations (phonic productions) that are commonly present in children and are required symptoms for the diagnosis of Tourette syndrome. Despite their frequency, the underlying pathophysiology of tics/Tourette syndrome remains unknown. In this review, we discuss a variety of controversies surrounding the pathophysiology of tics, including the following: Are tics voluntary or involuntary? What is the role of the premonitory urge? Are tics due to excess excitatory or deficient inhibition? Is it time to adopt the contemporary version of the cortico-basal ganglia-thalamocortical (CBGTC) circuit? and Do we know the primary abnormal neurotransmitter in Tourette syndrome? Data from convergent clinical and animal model studies support complex interactions among the various CBGTC sites and neurotransmitters. Advances are being made; however, numerous pathophysiologic questions persist.

Tics and Tourette Syndrome.

PURPOSE OF REVIEW: The purpose of this article is to present current information on the phenomenology, epidemiology, comorbidities, and pathophysiology of tic disorders and discuss therapy options. It is hoped that a greater understanding of each of these components will provide clinicians with the necessary information to deliver thoughtful and optimal care to affected individuals. RECENT FINDINGS: Recent advances include the finding that Tourette syndrome is likely due to a combination of several different genes, both low-effect and larger-effect variants, plus environmental factors. Pathophysiologically, increasing evidence supports involvement of the cortical-basal ganglia-thalamocortical circuit; however, the primary location and neurotransmitter remain controversial. Behavioral therapy is first-line treatment, and pharmacotherapy is based on tic severity. Several newer therapeutic agents are under investigation (eg, valbenazine, deutetrabenazine, cannabinoids), and deep brain stimulation is a promising therapy. SUMMARY: Tics, defined as sudden, rapid, recurrent, nonrhythmic motor movements or vocalizations, are essential components of Tourette syndrome. Although some tics may be mild, others can cause significant psychosocial, physical, and functional difficulties that affect daily activities. In addition to tics, most affected individuals have coexisting neuropsychological difficulties (attention deficit hyperactivity disorder, obsessive-compulsive disorder, anxiety, mood disorder, disruptive behaviors, schizotypal traits, suicidal behavior, personality disorder, antisocial activities, and sleep disorders) that can further impact social and academic activities or employment.

Intracranial calcifications and dystonia associated with a novel deletion of chromosome 8p11.2 encompassing SLC20A2 and THAP1.

Several genes located within the chromosome 8p11.21 region are associated with movement disorders including SLC20A2 and THAP1. SLC20A2 is one of four genes associated with primary familial brain calcification, a syndrome that also includes movement disorders, cognitive decline and psychiatric issues. THAP1 is associated with dystonia type 6, a dominantly inherited dystonia with variable expression. In addition, several reports in the French-Canadian population have described microdeletions within the 8p11.2 region presenting with dystonia-plus syndromes including brain calcifications. This case report describes a 12-year-old boy with brain calcifications and generalised dystonia associated with a deletion in the 8p11.2 region detected via single nucleotide polymorphism microarray. This report emphasises the importance of obtaining a microarray analysis in diagnosing movement disorders and suggests that this copy number variant may be an under-recognised cause of dystonia and brain calcifications.

Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies.

OBJECTIVE: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. METHODS: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. RESULTS: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. CONCLUSIONS: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.