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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., (© 2021. The Author(s).)

Tourette's Disorder (TD) is a neurodevelopmental disorder (NDD) that affects about 0.7% of the population and is one of the most heritable NDDs. Nevertheless, because of its polygenic nature and genetic heterogeneity, the genetic etiology of TD is not well understood. In this study, we combined the segregation information in 13 TD multiplex families with high-throughput sequencing and genotyping to identify genes associated with TD. Using whole-exome sequencing and genotyping array data, we identified both small and large genetic variants within the individuals. We then combined multiple types of evidence to prioritize candidate genes for TD, including variant segregation pattern, variant function prediction, candidate gene expression, protein-protein interaction network, candidate genes from previous studies, etc. From the 13 families, 71 strong candidate genes were identified, including both known genes for NDDs and novel genes, such as HtrA Serine Peptidase 3 (HTRA3), Cadherin-Related Family Member 1 (CDHR1), and Zinc Finger DHHC-Type Palmitoyltransferase 17 (ZDHHC17). The candidate genes are enriched in several Gene Ontology categories, such as dynein complex and synaptic membrane. Candidate genes and pathways identified in this study provide biological insight into TD etiology and potential targets for future studies., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Explosive outbursts occur in 25%-70% of children with Tourette syndrome (TS) and may cause more distress than the tics themselves. Previous studies have indicated that a comorbid diagnosis of attention-deficit/hyperactivity disorder (ADHD) is associated with emotional dysregulation in TS; however, this relationship has almost exclusively been studied using parent-reported questionnaires., Methods: We examined emotion regulation (ER) with an observational measure in 150 medication-naïve children aged 7-12 allocated to four groups: Forty-nine children with TS, 23 children with ADHD, 16 children with TS + ADHD, and 62 typically developing controls. We assessed participants' ER ability, as well as parent-child interactions in the context of a complex puzzle task, and coded the observed behavior with the Tangram Emotion Coding Manual (TEC-M). We examined group differences in ER, as well as associations between ER and severity of symptoms pertaining to TS and ADHD., Results: Children with TS did not differ from controls in their ER ability. However, children with ADHD and TS + ADHD had more problems with ER than those with TS only and controls. Finally, parents of children with ADHD displayed more tension during the experimental task. ER ability was not associated with tic severity nor premonitory urges; however, better ER ability was associated with less severe symptoms of ADHD., Conclusions: This study is the first to evaluate ER with an observational, clinician-rated measure in a controlled social setting in children with TS. Our findings support earlier questionnaire-based studies by showing impaired ER in children with TS + ADHD, but not in children with TS without comorbidity. These findings inform our understanding of the phenomenology of emotional dysregulation in TS and the role of comorbid disorders., (© 2020 Association for Child and Adolescent Mental Health.)

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.

Background and Objectives: Difficulties in emotion regulation (ER) have been associated with several psychiatric disorders, emphasizing a need for a greater understanding of the concept and its associations with disruptive behavior. We aimed to study the ER strategy of cognitive reappraisal with an experimental test to increase our knowledge of emotional processes in child psychopathology., Methods: In the present study, we examined emotional reactivity and cognitive reappraisal with a computer task in 160 medication-naïve children aged 8-12 comprising four groups: Fifty-eight children with Tourette syndrome (TS), 26 children with attention-deficit/hyperactivity disorder (ADHD), 19 children with TS and ADHD, and 57 typically developing controls., Results: The use of cognitive reappraisal reduced negative affect across all participants and the ability to reappraise was positively correlated with age, whereas reactivity was not. Overall, groups did not differ in reactivity or regulation success. Looking at specific differences within groups, however, only the ADHD group did not significantly decrease negative affect when reappraising. Finally, the use of strategies considered to be efficacious was correlated with regulation success, whereas the use of a less adaptive strategy related to suppression was associated with reactivity, but not regulation of emotions., Limitations: The study was limited by small, clinical contrast groups and a lack of blinding to diagnostic status in the coding of verbal strategies employed during the task., Conclusions: Cognitive reappraisal appears to be a beneficial ER strategy for children regardless of diagnostic status. Our findings indicate that children can learn and employ an adaptive ER strategy when instructed in the technique, even in the presence of attention problems, which is highly relevant to therapeutic approaches to dysregulated behavior., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In children with Tourette syndrome (TS), tics are often attributed to deficient self-control by health-care professionals, parents, and peers. In this behavioural study, we examined response inhibition in TS using a modified Simon task which probes the ability to solve the response conflict between a new non-spatial rule and a highly-overlearned spatial stimulus-response mapping rule. We applied a distributional analysis to the behavioural data, which grouped the trials according to the individual distribution of reaction times in four time bins. Distributional analyses enabled us to probe the children's ability to control fast, impulsive, responses, which corresponded to the trials in the fastest time bin. Additionally, we tested whether the ability to suppress inappropriate action tendencies can be improved further by the prospect of a reward. Forty-one clinically well-characterized medication-naïve children with TS, 20 children with attention-deficit/hyperactivity disorder (ADHD), and 43 typically developing children performed a Simon task during alternating epochs with and without a prospect of reward. We applied repeated measures ANCOVAs to estimate how the prospect of reward modulated reaction times and response accuracy, while taking into account the distribution of the reaction times across trials. We found between-group differences in accuracy when subjects responded relatively fast. The TS group responded more accurately than typically developing control children when resolving the response conflict introduced by the Simon task. The opposite pattern was found in children with ADHD. Prospect of reward improved accuracy rates in all groups. Although the Tourette group performed with superior accuracy in the fast trials, it was still possible for them to benefit from prospect of reward in fast trials. The findings corroborate the notion that children with TS have an enhanced capacity to inhibit fast inappropriate response tendencies. This ability can be improved further by offering a prospect of reward which might be useful during non-pharmacological therapeutic interventions., (Copyright © 2019. Published by Elsevier Ltd.)

Pre- and perinatal complications have been implicated in the onset and clinical expression of Tourette syndrome albeit with considerable inconsistencies across studies. Also, little is known about their role in co-occurring obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in individuals with a tic disorder. Therefore, we aimed to investigate the role of pre- and perinatal complications in relation to the presence and symptom severity of chronic tic disorder and co-occurring OCD and ADHD using data of 1113 participants from the Tourette International Collaborative Genetics study. This study included 586 participants with a chronic tic disorder and 527 unaffected family controls. We controlled for age and sex differences by creating propensity score matched subsamples for both case-control and within-case analyses. We found that premature birth (OR = 1.72) and morning sickness requiring medical attention (OR = 2.57) were associated with the presence of a chronic tic disorder. Also, the total number of pre- and perinatal complications was higher in those with a tic disorder (OR = 1.07). Furthermore, neonatal complications were related to the presence (OR = 1.46) and severity (b = 2.27) of co-occurring OCD and also to ADHD severity (b = 1.09). Delivery complications were only related to co-occurring OCD (OR = 1.49). We conclude that early exposure to adverse situations during pregnancy is related to the presence of chronic tic disorders. Exposure at a later stage, at birth or during the first weeks of life, appears to be associated with co-occurring OCD and ADHD., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The exact etiology of Tourette Syndrome (TS) remains unclear, making the search for impaired neuropsychological functions possibly connected to the underlying cause of TS as important as it is challenging. One neuropsychological domain of interest is fine motor skills.

Pre- and perinatal complications have been implicated in the onset and clinical expression of Tourette syndrome albeit with considerable inconsistencies across studies. Also, little is known about their role in co-occurring obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in individuals with a tic disorder. Therefore, we aimed to investigate the role of pre- and perinatal complications in relation to the presence and symptom severity of chronic tic disorder and co-occurring OCD and ADHD using data of 1113 participants from the Tourette International Collaborative Genetics study. This study included 586 participants with a chronic tic disorder and 527 unaffected family controls. We controlled for age and sex differences by creating propensity score matched subsamples for both case-control and within-case analyses. We found that premature birth (OR = 1.72) and morning sickness requiring medical attention (OR = 2.57) were associated with the presence of a chronic tic disorder. Also, the total number of pre- and perinatal complications was higher in those with a tic disorder (OR = 1.07). Furthermore, neonatal complications were related to the presence (OR = 1.46) and severity (b = 2.27) of co-occurring OCD and also to ADHD severity (b = 1.09). Delivery complications were only related to co-occurring OCD (OR = 1.49). We conclude that early exposure to adverse situations during pregnancy is related to the presence of chronic tic disorders. Exposure at a later stage, at birth or during the first weeks of life, appears to be associated with co-occurring OCD and ADHD.

Tourette Syndrome (TS) has previously been associated with deficits in inhibitory control (IC). However, studies on IC in individuals with TS have produced conflicting results. In the present study, we investigated IC, comparing the Stop Signal Reaction Time (SSRT) measure with parent and teacher ratings of daily life IC in 169 children aged 8–12 (60 with TS, 60 typically developing controls, 27 with attention-deficit/hyperactivity disorder (ADHD), and 22 with TS + ADHD). We further investigated associations of IC with TS and ADHD symptom severity. Children with TS showed intact SSRT performance, but impairments in daily life IC, as reported by parents and teachers. For the latter, we observed a staircase distribution of groups, with the healthy controls presenting with the best IC, followed by TS, TS + ADHD, and finally ADHD. Dimensional analyses indicated a strong association between ADHD severity and both measures of IC. Our results indicate that children with TS are not impaired in a laboratory-based measure of IC, although some difficulties were evident from measures of everyday behaviour, which may in part be due to parents and teachers interpreting tics as disinhibited behaviour. Comorbid ADHD or the severity of subthreshold ADHD symptomatology appeared to account for IC deficits. [ABSTRACT FROM AUTHOR]