Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent–child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case–control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive–compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes

Lack of Association of Group A Streptococcal Infections and Onset of Tics: European Multicenter Tics in Children Study

Background and objectives: The goal of this work was to investigate the association between group A streptococcal (GAS) infections and tic incidence among unaffected children with a family history of chronic tic disorders (CTDs). Methods: In a prospective cohort study, children with no history for tics who were 3 to 10 years of age with a first-degree relative with a CTD were recruited from the European Multicentre Tics in Children Study (EMTICS) across 16 European centers. Presence of GAS infection was assessed with throat swabs, serum anti-streptolysin O titers, and anti-DNAse titers blinded to clinical status. GAS exposure was defined with 4 different definitions based on these parameters. Cox regression analyses with time-varying GAS exposure were conducted to examine the association of onset of tics and GAS exposure during follow-up. Sensitivity analyses were conducted with Cox regression and logistic regression analyses. Results: A total of 259 children were recruited; 1 child was found to have tic onset before study entry and therefore was excluded. Sixty-one children (23.6%) developed tics over an average follow-up period of 1 (SD 0.7) year. There was a strong association of sex and onset of tics, with girls having an ≈60% lower risk of developing tics compared to boys (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.2-0.7). However, there was no statistical evidence to suggest an association of any of the 4 GAS exposure definitions with tic onset (GAS exposure definition 1: HR 0.310, 95% CI 0.037-2.590; definition 2: HR 0.561, 95% CI 0.219-1.436; definition 3: HR 0.853, 95% CI 0.466-1.561; definition 4: HR 0.725, 95% CI 0.384-1.370). Discussion: These results do not suggest an association between GAS exposure and development of tics. Classification of evidence: This study provides Class I evidence that group A streptococcal exposure does not associate with the development of tics in children with first-degree relatives with chronic tic disorder

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

The relation between attention and tic generation in Tourette syndrome

OBJECTIVE: Many neuropsychiatric disorders involve abnormal attentional processing. Systematic investigations of how attention may affect tic frequency in Tourette syndrome are lacking.METHOD: Patients performed rhythmic finger movements, approximately once every 2 s. Each movement triggered a unique visual color stimulus. Patients were asked to monitor and remember their finger actions, the external colors caused by their actions, or their tics. Sixteen adult Tourette syndrome patients performed each task twice: once while inhibiting tics, and once without inhibiting tics.RESULTS: During the "freely tic" condition, patients had significantly fewer tics when attending to finger movements, or to the ensuing colors, compared with when attending to their tics. Attention to fingers produced the fewest tics overall. During tic suppression, tic frequency was reduced to an equal level in all conditions.CONCLUSIONS: Focusing attention away from tics significantly reduces tic frequency. This attentional process may operate by regulating motor noise.</p

Altered perceptual binding in Gilles de la Tourette syndrome

Gilles de la Tourette syndrome (GTS) is a common multifaceted neuropsychiatric disorder. Research in GTS has traditionally focussed on mechanisms underlying changes in motor processes in these patients. There is, however, growing interest in GTS related sensory phenomena. According to the Theory of Event-coding (TEC), sensory stimuli do not only serve representational functions but also action-related functions. In the current study, we use the TEC framework to examine whether the way perceptual features are processed is altered in GTS. The results show that basic perceptual processes differ between GTS patients and healthy controls which might be central for the understanding of this disorder. Details or features of perceptual objects were less bound in GTS suggesting that perceptual features integration is attenuated in them. Behavioural findings were unrelated to patient characteristics implying that they might represent trait abnormalities. It is possible that altered perceptual processing in GTS is due to a long-range under-connectivity of parietal areas with other brain regions repeatedly been described in these patients.</p

Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive-compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate gene

The Premonitory Urge for Tics Scale in a large sample of children and adolescents: psychometric properties in a developmental context. An EMTICS study

Premonitory urges are uncomfortable physical sensations preceding tics that occur in most individuals with a chronic tic disorder. The Premonitory Urge for Tics Scale (PUTS) is the most frequently used self-report measure to assess the severity of premonitory urges. We aimed to evaluate the psychometric properties of the PUTS in the largest sample size to date (n = 656), in children aged 3–16 years, from the baseline measurement of the longitudinal European Multicenter Tics in Children Study (EMTICS). Our psychometric evaluation was done in three age-groups: children aged 3–7 years (n = 103), children between 8 and 10 years (n = 253), and children aged 11–16 years (n = 300). The PUTS exhibited good internal reliability in children and adolescents, also under the age of 10, which is younger than previously thought. We observed significant but small correlations between the severity of urges and severity of tics and obsessive–compulsive symptoms, and between severity of urges and ratings of attention-deficit/hyperactivity disorder and internalizing and externalizing behaviors, however, only in children of 8–10 years. Consistent with previous results, the 10th item of the PUTS correlated less with the rest of the scale compared to the other items and, therefore, should not be used as part of the questionnaire. We found a two-factor structure of the PUTS in children of 11 years and older, distinguishing between sensory phenomena related to tics, and mental phenomena as often found in obsessive–compulsive disorder. The age-related differences observed in this study may indicate the need for the development of an age-specific questionnaire to assess premonitory urges