Telemedicine-Based Cognitive Examinations During COVID-19 and Beyond: Perspective of the Massachusetts General Hospital Behavioral Neurology & Neuropsychiatry Group.

Telehealth and telemedicine have encountered explosive growth since the beginning of the COVID-19 pandemic, resulting in increased access to care for patients located far from medical centers and clinics. Subspecialty clinicians in behavioral neurology & neuropsychiatry (BNNP) have implemented the use of telemedicine platforms to perform cognitive examinations that were previously office based. In this perspective article, BNNP clinicians at Massachusetts General Hospital (MGH) describe their experience performing cognitive examinations via telemedicine. The article reviews the goals, prerequisites, advantages, and potential limitations of performing a video- or telephone-based telemedicine cognitive examination. The article shares the approaches used by MGH BNNP clinicians to examine cognitive and behavioral areas, such as orientation, attention and executive functions, language, verbal learning and memory, visual learning and memory, visuospatial function, praxis, and abstract abilities, as well as to survey for neuropsychiatric symptoms and assess activities of daily living. Limitations of telemedicine-based cognitive examinations include limited access to and familiarity with telecommunication technologies on the patient side, limitations of the technology itself on the clinician side, and the limited psychometric validation of virtual assessments. Therefore, an in-person examination with a BNNP clinician or a formal in-person neuropsychological examination with a neuropsychologist may be recommended. Overall, this article emphasizes the use of standardized cognitive and behavioral assessment instruments that are either in the public domain or, if copyrighted, are nonproprietary and do not require a fee to be used by the practicing BNNP clinician.

Convergent imaging-transcriptomic evidence for disturbed iron homeostasis in Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric movement disorder with reported abnormalities in various neurotransmitter systems. Considering the integral role of iron in neurotransmitter synthesis and transport, it is hypothesized that iron exhibits a role in GTS pathophysiology. As a surrogate measure of brain iron, quantitative susceptibility mapping (QSM) was performed in 28 patients with GTS and 26 matched controls. Significant susceptibility reductions in the patients, consistent with reduced local iron content, were obtained in subcortical regions known to be implicated in GTS. Regression analysis revealed a significant negative association of tic scores and striatal susceptibility. To interrogate genetic mechanisms that may drive these reductions, spatially specific relationships between susceptibility and gene-expression patterns from the Allen Human Brain Atlas were assessed. Correlations in the striatum were enriched for excitatory, inhibitory, and modulatory neurochemical signaling mechanisms in the motor regions, mitochondrial processes driving ATP production and iron­sulfur cluster biogenesis in the executive subdivision, and phosphorylation-related mechanisms affecting receptor expression and long-term potentiation in the limbic subdivision. This link between susceptibility reductions and normative transcriptional profiles suggests that disruptions in iron regulatory mechanisms are involved in GTS pathophysiology and may lead to pervasive abnormalities in mechanisms regulated by iron-containing enzymes.

Elevated common variant genetic risk for tourette syndrome in a densely-affected pedigree.

Tourette syndrome (TS) is a highly heritable neuropsychiatric disorder with complex patterns of genetic inheritance. Recent genetic findings in TS have highlighted both numerous common variants with small effects and a few rare variants with moderate or large effects. Here we searched for genetic causes of TS in a large, densely-affected British pedigree using a systematic genomic approach. This pedigree spans six generations and includes 122 members, 85 of whom were individually interviewed, and 53 of whom were diagnosed as "cases" (consisting of 28 with definite or probable TS, 20 with chronic multiple tics [CMT], and five with obsessive-compulsive behaviors [OCB]). A total of 66 DNA samples were available (25 TS, 15 CMT, 4 OCB cases, and 22 unaffecteds) and all were genotyped using a dense single nucleotide polymorphism (SNP) array to identify shared segments, copy number variants (CNVs), and to calculate genetic risk scores. Eight cases were also whole genome sequenced to test whether any rare variants were shared identical by descent. While we did not identify any notable CNVs, single nucleotide variants, indels or repeat expansions of near-Mendelian effect, the most distinctive feature of this family proved to be an unusually high load of common risk alleles for TS. We found that cases within this family carried a higher load of TS common variant risk similar to that previously found in unrelated TS cases. Thus far, the strongest evidence from genetic data for contribution to TS risk in this family comes from multiple common risk variants rather than one or a few variants of strong effect.

Is Persistent Motor or Vocal Tic Disorder a Milder Form of Tourette Syndrome?

BACKGROUND: Persistent motor or vocal tic disorder (PMVT) has been hypothesized to be a forme fruste of Tourette syndrome (TS). Although the primary diagnostic criterion for PMVT (presence of motor or vocal tics, but not both) is clear, less is known about its clinical presentation. OBJECTIVE: The goals of this study were to compare the prevalence and number of comorbid psychiatric disorders, tic severity, age at tic onset, and family history for TS and PMVT. METHODS: We analyzed data from two independent cohorts using generalized linear equations and confirmed our findings using meta-analyses, incorporating data from previously published literature. RESULTS: Rates of obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) were lower in PMVT than in TS in all analyses. Other psychiatric comorbidities occurred with similar frequencies in PMVT and TS in both cohorts, although meta-analyses suggested lower rates of most psychiatric disorders in PMVT compared with TS. ADHD and OCD increased the odds of comorbid mood, anxiety, substance use, and disruptive behaviors, and accounted for observed differences between PMVT and TS. Age of tic onset was approximately 2 years later, and tic severity was lower in PMVT than in TS. First-degree relatives had elevated rates of TS, PMVT, OCD, and ADHD compared with population prevalences, with rates of TS equal to or greater than PMVT rates. CONCLUSIONS: Our findings support the hypothesis that PMVT and TS occur along a clinical spectrum in which TS is a more severe and PMVT a less severe manifestation of a continuous neurodevelopmental tic spectrum disorder. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Examination of the shared genetic basis of anorexia nervosa and obsessive-compulsive disorder.

Anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) are often comorbid and likely to share genetic risk factors. Hence, we examine their shared genetic background using a cross-disorder GWAS meta-analysis of 3495 AN cases, 2688 OCD cases, and 18,013 controls. We confirmed a high genetic correlation between AN and OCD (rg = 0.49 ± 0.13, p = 9.07 × 10-7) and a sizable SNP heritability (SNP h2 = 0.21 ± 0.02) for the cross-disorder phenotype. Although no individual loci reached genome-wide significance, the cross-disorder phenotype showed strong positive genetic correlations with other psychiatric phenotypes (e.g., rg = 0.36 with bipolar disorder and 0.34 with neuroticism) and negative genetic correlations with metabolic phenotypes (e.g., rg = -0.25 with body mass index and -0.20 with triglycerides). Follow-up analyses revealed that although AN and OCD overlap heavily in their shared risk with other psychiatric phenotypes, the relationship with metabolic and anthropometric traits is markedly stronger for AN than for OCD. We further tested whether shared genetic risk for AN/OCD was associated with particular tissue or cell-type gene expression patterns and found that the basal ganglia and medium spiny neurons were most enriched for AN-OCD risk, consistent with neurobiological findings for both disorders. Our results confirm and extend genetic epidemiological findings of shared risk between AN and OCD and suggest that larger GWASs are warranted.

Investigation of gene-environment interactions in relation to tic severity.

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene-environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene-environment studies.

Bridging the Great Divide: What Can Neurology Learn From Psychiatry?

Neurology and psychiatry share common historical origins and rely on similar tools to study brain disorders. Yet the practical integration of medical and scientific approaches across these clinical neurosciences remains elusive. Although much has been written about the need to incorporate emerging systems-level, cellular-molecular, and genetic-epigenetic advances into a science of mind for psychiatric disorders, less attention has been given to applying clinical neuroscience principles to conceptualize neurologic conditions with an integrated neurobio-psycho-social approach. In this perspective article, the authors briefly outline the historically interwoven and complicated relationship between neurology and psychiatry. Through a series of vignettes, the authors then illustrate how some traditional psychiatric conditions are being reconceptualized in part as disorders of neurodevelopment and awareness. They emphasize the intersection of neurology and psychiatry by highlighting conditions that cut across traditional diagnostic boundaries. The authors argue that the divide between neurology and psychiatry can be narrowed by moving from lesion-based toward circuit-based understandings of neuropsychiatric disorders, from unidirectional toward bidirectional models of brain-behavior relationships, from exclusive reliance on categorical diagnoses toward transdiagnostic dimensional perspectives, and from silo-based research and treatments toward interdisciplinary approaches. The time is ripe for neurologists and psychiatrists to implement an integrated clinical neuroscience approach to the assessment and management of brain disorders. The subspecialty of behavioral neurology & neuropsychiatry is poised to lead the next generation of clinicians to merge brain science with psychological and social-cultural factors. These efforts will catalyze translational research, revitalize training programs, and advance the development of impactful patient-centered treatments.

Prevalence and predictors of hair pulling disorder and excoriation disorder in Tourette syndrome.

Trichotillomania/hair pulling disorder (HPD) and excoriation/skin picking disorder (SPD) are childhood-onset, body-focused repetitive behaviors that are thought to share genetic susceptibility and underlying pathophysiology with obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). We sought to determine the prevalence of DSM-5 HPD and SPD in TS patients, and to identify clinical factors most associated with their co-morbidity with TS. Participants included 811 TS patients recruited from TS specialty clinics for a multi-center genetic study. Patients were assessed using standardized, validated semi-structured interviews. HPD and SPD diagnoses were determined using a validated self-report questionnaire. HPD/SPD prevalence rates were calculated, and clinical predictors were evaluated using regression modeling. 3.8 and 13.0% of TS patients met DSM-5 criteria for HPD and SPD, respectively. In univariable analyses, female sex, OCD, and both tic and obsessive-compulsive symptom severity were among those associated with HPD and/or SPD. In multivariable analyses, only lifetime worst-ever motor tic severity remained significantly associated with HPD. Female sex, co-occurring OCD, ADHD, and motor tic severity remained independently associated with SPD. This is the first study to examine HPD and SPD prevalence in a TS sample using semi-structured diagnostic instruments. The prevalence of HPD and SPD in TS patients, and their association with increased tic severity and co-occurring OCD, suggests that clinicians should screen children with TS and related disorders for HPD/SPD, particularly in females and in those with co-occurring OCD. This study also helps set a foundation for subsequent research regarding HPD/SPD risk factors, pathophysiology, and treatment models.

Predictors of comorbid eating disorders and association with other obsessive-compulsive spectrum disorders in trichotillomania.

Trichotillomania (TTM) and eating disorders (ED) share many phenomenological similarities, including ritualized compulsive behaviors. Given this, and that comorbid EDs may represent additional functional burden to hair pullers, we sought to identify factors that predict diagnosis of an ED in a TTM population. Subjects included 555 adult females (age range 18-65) with DSM-IV-TR TTM or chronic hair pullers recruited from multiple sites. 7.2% (N=40) of our TTM subjects met criteria for an ED in their lifetime. In univariable regression analysis, obsessive-compulsive disorder (OCD), Yale-Brown Obsessive Compulsive Scale (Y-BOCS) worst-ever compulsion and total scores, certain obsessive-compulsive spectrum disorders, anxiety disorder, attention-deficit/hyperactivity disorder (ADHD), and substance disorder all met the pre-specified criteria for inclusion in the multivariable analysis. In the final multivariable model, diagnosis of OCD (OR: 5.68, 95% CI: 2.2-15.0) and diagnosis of an additional body-focused repetitive behavior disorder (BFRB) (OR: 2.69, 95% CI: 1.1-6.8) were both associated with increased risk of ED in TTM. Overall, our results provide further support of the relatedness between ED and TTM. This finding highlights the importance of assessing for comorbid OCD and additional BFRBs in those with TTM. Future research is needed to identify additional predictors of comorbid disorders and to better understand the complex relationships between BFRBs, OCD and EDs.

Predictors of comorbid obsessive-compulsive disorder and skin-picking disorder in trichotillomania.

BACKGROUND: Trichotillomania (TTM), obsessive-compulsive disorder (OCD), and skin-picking disorder (SPD) frequently occur together and share overlapping phenomenology, pathophysiology, and possible genetic underpinnings. This study sought to identify factors that predict OCD and SPD in hair pullers. METHODS: Five hundred fifty-five adult female hair pullers were recruited from specialty clinics and assessed using standardized, semi-structured interviews and self-reports. Clinical predictors and multivariate models were evaluated using logistic regression modeling. RESULTS: Hair pullers met criteria for OCD (18.9%), SPD (19.5%), or chronic skin picking (CSP) (5%), or both comorbid diagnoses, respectively. In the final multivariate model for OCD, family history of OCD and an eating disorder diagnosis were associated with an increased risk of OCD in TTM. A nail-biting diagnosis was associated with a decreased risk of OCD in TTM. In the final multivariate model for SPD/CSP, only family history of OCD was associated with an increased risk of SPD/CSP in TTM. CONCLUSIONS: Identification of factors predicting OCD and SPD in TTM provides evidence for the relatedness of these disorders and supports their collective classification as obsessive-compulsive and related disorders (OCRDs) in DSM-5. The findings of this study further underscore the importance of assessing for comorbid OCRDs and family histories of OCRDs in clinical practice.

Genetic association signal near NTN4 in Tourette syndrome.

Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10(-3) ) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry-matched controls. Only rs2060546 on chromosome 12q22 (p = 3.3 × 10(-4) ) remained significant after Bonferroni correction. Meta-analysis with the original GWAS yielded the strongest association to date (p = 5.8 × 10(-7) ). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case-control status (p = 0.042), suggesting that many of these variants are true TS risk alleles.

Population prevalence of Tourette syndrome: a systematic review and meta-analysis.

The aim of this study was to refine the population prevalence estimate of Tourette Syndrome (TS) in children and to investigate potential sources of heterogeneity in previously published studies. A systematic review was conducted and all qualifying published studies of TS prevalence were examined. Extracted data were subjected to a random-effects meta-analysis weighted by sample size; meta-regressions were performed to examine covariates that have previously been proposed as potential sources of heterogeneity. Twenty-six articles met study inclusion criteria. Studies derived from clinically referred cases had prevalence estimates that were significantly lower than those derived from population-based samples (P = 0.004). Among the 21 population-based prevalence studies, the pooled TS population prevalence estimate was 0.52% (95% confidence interval CI: 0.32-0.85). In univariable meta-regression analysis, study sample size (P = 0.002) and study date (P = 0.03) were significant predictors of TS prevalence. In the final multivariable model including sample size, study date, age, and diagnostic criteria, only sample size (P < 0.001) and diagnostic criteria (omnibus P = 0.003; Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR]: P = 0.005) were independently associated with variation in TS population prevalence across studies. This study refines the population prevalence estimate of TS in children to be 0.3% to 0.9%. Study sample size, which is likely a proxy for case assessment method, and the use of DSM-IV-TR diagnostic criteria are the major sources of heterogeneity across studies. The true TS population prevalence rate is likely at the higher end of these estimates, given the methodological limitations of most studies. Further studies in large, well-characterized samples will be helpful to determine the burden of disease in the general population.

Association between pre- and perinatal exposures and Tourette syndrome or chronic tic disorder in the ALSPAC cohort.

BACKGROUND: Tourette syndrome and chronic tic disorder are heritable but aetiologically complex. Although environment plays a role in their development, existing studies of non-genetic risk factors are inconsistent. AIMS: To examine the association between pre- and perinatal exposures and Tourette syndrome/chronic tic disorder in the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective longitudinal pre-birth cohort. METHOD: Relationships between exposures and Tourette syndrome/chronic tic disorder were examined in 6090 children using logistic regression. RESULTS: Maternal alcohol and cannabis use, inadequate maternal weight gain and parity were associated with Tourette syndrome or Tourette syndrome/chronic tic disorder. Other previously reported exposures, including birth weight and prenatal maternal smoking, were not associated with Tourette syndrome/chronic tic disorder. CONCLUSIONS: This study supports previously reported relationships between Tourette syndrome/chronic tic disorder and prenatal alcohol exposure, and identifies additional previously unexplored potential prenatal risk factors.

Tourette syndrome and chronic tic disorder are associated with lower socio-economic status: findings from the Avon Longitudinal Study of Parents and Children cohort.

AIM: Only a few studies have examined the relationship between Tourette syndrome or chronic tic disorder and socio-economic status (SES). Existing studies are primarily cross-sectional, arise from specialty clinics, and use single measures of SES. In this study we examine this relationship in a longitudinal, population-based sample. METHOD: Data are from 7152 children born during 1991 and 1992 in the county of Avon, UK, from the Avon Longitudinal Study of Parents and Children, who were followed up to age 13. After exclusions for intellectual disability* and autism, 6768 participants (3351 males [49.5%]) and 3417 females [50.5%]) remained. Parental SES was assessed using multiple measures during pregnancy and at 33 months of age. Presence of Tourette syndrome or chronic tics was determined from repeated maternal questionnaires up to when the child was 13 years of age. RESULTS: Multiple SES measures were associated with an approximately twofold increased risk of Tourette syndrome and chronic tics. A postnatal composite factor score (lowest vs highest tertile odds ratio 2.09, 95% confidence interval 1.38-3.47) provided the best fit to the data. INTERPRETATIONS: As is seen in several childhood conditions, such as cerebral palsy and autism, lower SES is a risk factor for Tourette syndrome/chronic tics. Potential explanations include differential exposure to environmental risk factors or parental psychopathology as a measure of an increased genetic risk leading to decreased parental SES.

Increase in Functional Tic Presentations in Sexual Orientation and Gender Identity Minority Youth During Coronavirus Disease 2019.

BACKGROUND: Functional tic disorders are among the least common functional movement disorders, but their prevalence rose during the coronavirus disease 2019 (COVID-19) pandemic. Although female adolescents develop functional neurological disorders at higher rates than males, investigations into sexual orientation and gender identity (SOGI) status of these patients are limited. METHODS: We completed a retrospective, cross-sectional time series examining the incidence of new-onset functional tic disorders in youth presenting to the Massachusetts General Hospital Movement Disorder clinics before and during the COVID-19 pandemic. Data were collected by searching for relevant International Classification of Diseases (ICD)-10 diagnostic codes in youth aged nine to 26 years using a hospital-wide data repository. Individual cases were reviewed for inclusion based on clinical criteria and expert consensus. RESULTS: The prevalence of functional tic presentations in youth rose 8.6-fold from pre- to postpandemic levels (Fisher exact test P < 0.001), whereas the prevalence of developmental tic presentations pre- and postpandemic remained stable (114 vs 112). SOGI minority youth comprised 37% of those with functional tics (total n = 19). Ninety five percent of patients with functional tics identified as female, with 10% of these identifying as transgender. CONCLUSIONS: Our data confirm previously demonstrated dramatic rises in functional tic presentations during the COVID-19 pandemic and, more notably, reveal a strong association with SOGI minority status. We highlight the potential link between functional tic disorders and SOGI minority status. Providing a safe and supportive clinical environment and addressing stress linked to SOGI minority status may help to improve patient prognosis.

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.

Developing a Phenotype Risk Score for Tic Disorders in a Large, Clinical Biobank.

Importance: Tics are a common feature of early-onset neurodevelopmental disorders, characterized by involuntary and repetitive movements or sounds. Despite affecting up to 2% of young children and having a genetic contribution, the underlying causes remain poorly understood, likely due to the complex phenotypic and genetic heterogeneity among affected individuals. Objective: In this study, we leverage dense phenotype information from electronic health records to identify the disease features associated with tic disorders within the context of a clinical biobank. These disease features are then used to generate a phenotype risk score for tic disorder. Design: Using de-identified electronic health records from a tertiary care center, we extracted individuals with tic disorder diagnosis codes. We performed a phenome-wide association study to identify the features enriched in tic cases versus controls (N=1,406 and 7,030; respectively). These disease features were then used to generate a phenotype risk score for tic disorder, which was applied across an independent set of 90,051 individuals. A previously curated set of tic disorder cases from an electronic health record algorithm followed by clinician chart review was used to validate the tic disorder phenotype risk score. Main Outcomes and Measures: Phenotypic patterns associated with a tic disorder diagnosis in the electronic health record. Results: Our tic disorder phenome-wide association study revealed 69 significantly associated phenotypes, predominantly neuropsychiatric conditions, including obsessive compulsive disorder, attention-deficit hyperactivity disorder, autism, and anxiety. The phenotype risk score constructed from these 69 phenotypes in an independent population was significantly higher among clinician-validated tic cases versus non-cases. Conclusions and Relevance: Our findings provide support for the use of large-scale medical databases to better understand phenotypically complex diseases, such as tic disorders. The tic disorder phenotype risk score provides a quantitative measure of disease risk that can be leveraged for the assignment of individuals in case-control studies or for additional downstream analyses.

Convergent imaging-transcriptomic evidence for disturbed iron homeostasis in Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric movement disorder with reported abnormalities in various neurotransmitter systems. Considering the integral role of iron in neurotransmitter synthesis and transport, it is hypothesized that iron exhibits a role in GTS pathophysiology. As a surrogate measure of brain iron, quantitative susceptibility mapping (QSM) was performed in 28 patients with GTS and 26 matched controls. Significant susceptibility reductions in the patient cohort, consistent with reduced local iron content, were obtained in subcortical regions known to be implicated in GTS. Regression analysis revealed a significant negative association of tic scores and striatal susceptibility. To interrogate genetic mechanisms that may drive these reductions, spatially specific relationships between susceptibility and gene-expression patterns extracted from the Allen Human Brain Atlas were assessed. Correlations in the striatum were enriched for excitatory, inhibitory, and modulatory neurochemical signaling mechanisms in the motor regions, mitochondrial processes driving ATP production and iron-sulfur cluster biogenesis in the executive subdivision, and phosphorylation-related mechanisms that affect receptor expression and long-term potentiation. This link between susceptibility reductions and normative transcriptional profiles suggests that disruptions in iron regulatory mechanisms are involved in GTS pathophysiology and may lead to pervasive abnormalities in mechanisms regulated by iron-containing enzymes.

Genome-wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome.

BACKGROUND: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. METHODS: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. RESULTS: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. CONCLUSIONS: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome.

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.