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.

Psychopathology and mental health service use among youth in foster care admitted to a psychiatric inpatient unit: a 4-year retrospective controlled study.

Youth in foster care (FC) are at increased risk of poor psychosocial outcomes. The aim of this study was to assess psychopathology and mental health service use among youth living in FC who require psychiatric hospitalisation. All individuals admitted to our Children and Adolescent Inpatient Psychiatry Unit between 2014 and 2017 who were in FC were systematically reviewed. The control group was defined as all youth living with their immediate family and hospitalised in our unit throughout 2016. We identified 89 patients placed in FC and 247 controls. Socio-demographic and clinical data were retrospectively collected from computerised charts. A survival analysis of emergency department visits and readmission to the hospital was conducted. Compared to controls, the FC group presented significantly higher rates of conduct disorder (78.7% vs 14.6%; p < 0.001) and substance use disorder (49.4% vs 27.5%; p < 0.001), mainly cannabis use (34.8% vs 16.6%; p < 0.001); higher rates of comorbidity (96.6% vs 55.9%; p < 0.001) and mean number of comorbid diagnoses (3.3 ± 1.1 vs 2.3 ± 0.5; p < 0.001). The FC group had a higher number of emergency room visits before and after admission than controls. FC youth were also 2.77 times more likely to visit the emergency department after discharge, and in a shorter time period, than controls (p = 0.004). Disruptive behaviours, substance use disorder, and comorbid psychopathology were all more prevalent among FC youth than controls. Specific strategies are needed to optimize community mental health resources and address the increased use of emergency services by these youth before and after hospitalisation.

Functional impairment in a Spanish Sample of Children and Adolescents with Obsessive-Compulsive Disorder.

The Child Obsessive-Compulsive Impact Scale (COIS-R) is a parent- and self-report measure of the impairment related to Obsessive-Compulsive Disorder (OCD) symptoms. Previous research has demonstrated the reliability and validity of the original version of the COIS-R; to date, however, the scale has not been validated for use in Spanish samples of pediatric OCD. The present study aimed to assess the psychometric properties of this in a clinical sample of pediatric OCD (n = 91). Analyses of internal consistency, convergent and divergent validity were conducted. For both the COIS-R report scales estimates similar to those in the original instrument were obtained for internal consistency, test-retest reliability, and convergent validity. Thus, the Spanish version of the COIS-R seems to retain sound psychometric properties of its original version; it appears to be a reliable instrument for the assessment of obsessive-compulsive impairment and the effects of treatment, and can be used in other cultural contexts.

Secretory immunoglobulin A (s-IgA) reactivity to acute psychosocial stress in children and adolescents: The influence of pubertal development and history of maltreatment.

BACKGROUND: Mucosal secretory immunoglobulin A (s-IgA) is an antibody protein-complex that plays a crucial role in immune first defense against infection. Although different immune biomarkers have been associated with stress-related psychopathology, s-IgA remains poorly studied, especially in youth. OBJECTIVES: The present study investigated how s-IgA behaves in front of acute psychosocial stress in children and adolescents, including possible variability associated with developmental stage and history of childhood maltreatment (CM). METHODS: 94 children and adolescents from 7 to 17 years (54 with a current psychiatric diagnostic and 40 healthy controls) drawn from a larger Spanish study were explored (EPI-Young Stress Project). To assess biological reactivity, participants provided five saliva samples during an acute laboratory-based psychosocial stressor, the Trier Social Stress Test for Children (TSST-C). Samples were assayed for s-IgA, as well as for cortisol. Pubertal development was ascertained by Tanner stage and CM following TASSCV criteria. RESULTS: We observed s-IgA fluctuations throughout the stressor, indicating the validity of TSST-C to stimulate s-IgA secretion (F(4,199) = 6.200, p <.001). Although s-IgA trajectories followed a reactivity and recovery pattern in adolescents, children exhibited no s-IgA response when faced with stress (F(4,197) = 3.406, p =.010). An interaction was found between s-IgA and CM (F(4,203) = 2.643, p =.035). Interestingly, an interaction between developmental stage, CM history and s-IgA reactivity was identified (F(12,343) = 2.036, p =.017); while children non-exposed to maltreatment exhibited no s-IgA changes to acute stress, children with a history of CM showed a similar response to adolescents, increasing their s-IgA levels after the psychosocial stressor. CONCLUSION: Acute psychosocial stress stimulates s-IgA secretion, but only after puberty. However, children with a history of maltreatment exhibited a response resembling that of adolescents, suggesting an early maturation of the immune system. Further studies are needed to clarify the validity of s-IgA as an acute stress biomarker, including additional measures during stress exposure.

Gene expression study in monocytes: evidence of inflammatory dysregulation in early-onset obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) has a complex etiology that seems to include immune dysfunction and alterations in circulating monocytes. To investigate the immune basis and the functional dysregulation of monocytes in this disease, we analyzed gene expression in the peripheral monocytes of pediatric patients with OCD (N = 102) compared to controls (N = 47). We examined gene expression in primary cultures of peripheral monocytes from participants, under basal conditions and under exposure to lipopolysaccharide (LPS) to stimulate immune response. Whole-genome expression was assessed in 8 patients and 8 controls. Differentially expressed genes were identified followed by protein-protein interaction network construction and functional annotation analysis to identify the genes and biological processes that are altered in the monocytes of OCD patients. We also explored the expression levels of selected genes in monocytes from the other participants using qPCR. Several changes in gene expression were observed in the monocytes of OCD patients, with several immune processes involved under basal conditions (antigen processing and presentation, regulation of immune system and leukocyte cell adhesion) and after LPS stimulation (immune and inflammatory response, cytokine production and leukocyte activation). Despite the qPCR analysis provided no significant differences between patients and controls, high correlations were observed between the expression levels of some of the genes and inflammatory markers (i.e., T helper 17 and regulatory T cell levels, total monocyte and proinflammatory monocyte subset levels, and the cytokine production by resting and stimulated monocytes) of the study participants. Our findings provide more evidence of the involvement of monocyte dysregulation in early-onset OCD, indicating a proinflammatory predisposition and an enhanced immune response to environmental triggers.

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.

Tic disorders in children and adolescents: does the clinical presentation differ in males and females? A report by the EMTICS group.

Tic disorders have a strong male predominance, with a male-to-female ratio of 4:1 in Tourette syndrome (TS) and 2:1 in persistent tic disorders. In other neurodevelopmental conditions, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), the disparity in sex distribution has been partially related to differences in symptom presentation between males and females. In tic disorders, however, little research has been conducted on this topic, probably due to the limited access to large samples with a significant proportion of females. The aim of this study was to describe sex differences in the clinical presentation of tic disorders in children and adolescents in one of the largest pediatric samples with TS/persistent tic disorders (n = 709, 23.3% females) recruited as part of the European Multicenter Tics in Children Study (EMTICS). Validated measures assessed the severity of tics and comorbid psychiatric symptoms. Using mixed-effect models, we found that sex had a significant influence on the severity of tics, ADHD symptoms, ASD symptoms, and emotional problems. Males had more severe symptoms than females, except for emotional problems. We also observed a statistically significant interaction between sex and age on the severity of tics and compulsions, with females showing higher symptom severity with increasing age than males. These findings indicate that the clinical presentation of TS/persistent tic disorders varies with sex. Males seem to exhibit a more noticeable pattern of clinical symptoms at a younger age that may contribute to their earlier detection in comparison to females.

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.

Whole-exome sequencing identifies genes associated with Tourette's disorder in multiplex families.

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.

Association of Group A Streptococcus Exposure and Exacerbations of Chronic Tic Disorders: A Multinational Prospective Cohort Study.

OBJECTIVE: To examine prospectively the association between group A Streptococcus (GAS) pharyngeal exposures and exacerbations of tics in a large multicenter population of youth with chronic tic disorders (CTD) across Europe. METHODS: We followed up 715 children with CTD (age 10.7 ± 2.8 years, 76.8% boys), recruited by 16 specialist clinics from 9 countries, and followed up for 16 months on average. Tic, obsessive-compulsive symptom (OCS), and attention-deficit/hyperactivity disorder (ADHD) severity was assessed during 4-monthly study visits and telephone interviews. GAS exposures were analyzed using 4 possible combinations of measures based on pharyngeal swab and serologic testing. The associations between GAS exposures and tic exacerbations or changes of tic, OC, and ADHD symptom severity were measured, respectively, using multivariate logistic regression plus multiple failure time analyses and mixed effects linear regression. RESULTS: A total of 405 exacerbations occurred in 308 of 715 (43%) participants. The proportion of exacerbations temporally associated with GAS exposure ranged from 5.5% to 12.9%, depending on GAS exposure definition. We did not detect any significant association of any of the 4 GAS exposure definitions with tic exacerbations (odds ratios ranging between 1.006 and 1.235, all p values >0.3). GAS exposures were associated with longitudinal changes of hyperactivity-impulsivity symptom severity ranging from 17% to 21%, depending on GAS exposure definition. CONCLUSIONS: This study does not support GAS exposures as contributing factors for tic exacerbations in children with CTD. Specific workup or active management of GAS infections is unlikely to help modify the course of tics in CTD and is therefore not recommended.

Visual memory improvement in adolescents at high risk for suicide who are receiving psychotherapy at a community clinic.

The current study aims to: 1) investigate cognitive differences among adolescents at risk for suicide versus healthy controls (HC) and 2) identify cognitive changes associated with response to psychotherapy among adolescents at high risk for suicide. Thirty-five adolescents at high risk for suicide (HR), and 14 HC adolescents were recruited. Clinical and cognitive assessments were conducted in both groups at baseline and 16 weeks later (after the patients completed psychotherapy). HR and HC adolescents were compared at baseline and at completion of the study. We also conducted further analysis by separating into two groups the HR adolescents who responded to psychotherapy (n=17) and those who did not (n=11). At baseline, the HR group had significantly lower performance on verbal memory and processing speed than the HC group. At week 16, HR adolescents performed as well as HC adolescents in all cognitive domains. Among patients, better performance on visual memory was observed in those who responded to psychotherapy compared to those who did not. We concluded that lower performance on verbal memory and processing speed may be associated with a high risk for suicide among adolescents. Improvement in visual memory might be related to a lower risk for suicide in adolescents.

Adapted Dialectical Behavior Therapy for Adolescents with a High Risk of Suicide in a Community Clinic: A Pragmatic Randomized Controlled Trial.

OBJECTIVE: This study is a pragmatic randomized controlled trial, which compares the effectiveness of an adapted form of Dialectical Behavior Therapy for Adolescents (DBT-A) and treatment as usual plus group sessions (TAU + GS) to reduce suicidal risk for adolescents in a community health mental clinic. METHOD: Thirty-five adolescents from a community outpatient clinic, with repetitive NSSI alone or with SA over the last 12 months and with current high suicide risk as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS), were enrolled. Participants were randomly assigned to undergo either DBT-A (n = 18) or TAU + GT (n = 17) treatments over a 16-week period. Primary outcomes were the difference between NSSI and SA recorded during the first 4 weeks and the final 4 weeks of treatment. Secondary outcomes included changes in Children's Global Assessment Scale (C-GAS), Suicidal Ideation Questionnaire (SIQ-JR), and Beck Depression Inventory-II (BDI-II). RESULTS: Dialectical Behavior Therapy for Adolescents was more effective than TAU + GS at reducing NSSI, use of antipsychotics, and improving C-GAS. No SAs were reported in the two groups at the end of the treatment. Both treatments were equally effective in decreasing SIQ-JR and BDI-II scores. CONCLUSIONS: These findings support the feasibility and effectiveness of DBT-A for adolescents at high risk of suicide in community settings.

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.

Altered frequencies of Th17 and Treg cells in children and adolescents with obsessive-compulsive disorder.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder with an etiopathophysiology that seems to include immune alterations. Previous studies have suggested that variations in the levels of circulating T cell subpopulations may be involved in psychiatric diseases. However, the role of these cells in OCD remains unexplored. Hence, the present study aimed to examine the levels of T helper 1 (Th1), Th2, Th17 and regulatory T (Treg) cells in patients with early-onset OCD and healthy controls. METHODS: The assessment was performed in 99 children and adolescents with OCD and 46 control subjects. The percentages of circulating Th1, Th2, Th17 and Treg cells were evaluated using flow cytometry. RESULTS: OCD patients had significantly higher levels of Th17 cells and lower percentages of Treg cells than healthy controls (p = 0.001 and p = 0.005, respectively). Furthermore, levels of Th17 cells progressively increased with the duration (p = 0.005) and severity of OCD (p = 0.008), whereas the percentages of Treg cells significantly declined with the duration of the disorder (p = 1.8 × 10-5). CONCLUSIONS: These results provide more evidence of the involvement of immune dysregulation, specifically an imbalance in the levels of circulating T helper and regulatory T cells, in the pathophysiology of early-onset OCD.

Fronto-Limbic Connectivity as a Predictor of Improvement in Nonsuicidal Self-Injury in Adolescents Following Psychotherapy.

Objectives: Key neurobiological factors contribute to vulnerability to nonsuicidal self-injury (NSSI) among adolescents and how they respond to treatment targeted to reduce such behaviors. This study aims to examine differences in intrinsic functional connectivity between adolescents with NSSI and healthy controls (HCs) and to identify baseline connectivity markers that predict improvements in NSSI after psychotherapy. Methods: Adolescents aged 12-17 (n = 24) with repetitive NSSI along with demographically similar HCs (n = 16) underwent resting-state functional MRI scanning after which patients received up to 4 months of psychological treatment. A seed-based approach was used to examine baseline between-group differences in intrinsic functional connectivity of the amygdala and the medial prefrontal cortex (mPFC). Further analyses examined the associations between intrinsic functional connectivity at baseline and improvement in NSSI after psychological treatment. Results: Compared with HCs, adolescents with NSSI showed significantly reduced connectivity between the amygdala and the anterior cingulate cortex, subcallosal cortex, and paracingulate gyrus, as well as between the amygdala and a cluster encompassing the right planum temporale and right insula. Adolescents with NSSI, compared with HCs, also showed reduced connectivity between the mPFC and two clusters: one located in the precentral and postcentral gyri and another in the left insula. After treatment, 50% of patients reported fewer NSSI episodes compared to baseline, which was considered as improvement. Stronger negative amygdala-prefrontal connectivity was associated with greater posttreatment improvement in NSSI. Conclusions: Adolescents with NSSI may have aberrant amygdala and mPFC connectivity compared with HCs. Furthermore, stronger baseline negative amygdala-prefrontal connectivity may predict greater improvement in NSSI after psychological intervention. Given that no prior study has used resting-state functional connectivity to predict response to psychological treatment in adolescents with NSSI, replication of these findings is needed.

Autoantibodies, elevated cytokines, and neurocognitive abnormalities in offspring of women with systemic lupus erythematosus: comparison with healthy controls.

INTRODUCTION: Research describes higher incidence of neurodevelopmental disorders and learning disabilities in offspring of women affected by lupus. Factors implied are pregnancy and delivery adversities and exposure to maternal antibodies and cytokines. Little is known about the offspring immunological condition or the relation between offspring and maternal condition. OBJECTIVES: This study was conducted in order to analyze immunological configuration, psychopathology, and neuropsychological performance of young offspring of women with lupus, in comparison with healthy controls and in relation to maternal psychophysical condition. METHODS: Twenty-one offspring aged 8-17 of 17 women with lupus and 34 controls were recruited. Pregnancy conditions, stress factors, and immunological, psychopathological, and neuropsychological characteristics were compared. Immunological tests included standard lupus screening, lupus-related autoantibodies, antibodies against GluN2 subunit of the N-methyl-D-aspartate receptor (NMDAR) (anti-DWEYS Ab), and levels of ten cytokines (IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, GMCSF, IFN-γ, TNF-α). RESULTS: Offspring had lower leukocyte count (p = 0.001) and higher levels of anti-dsDNA Ab (p = 0.022), anti-DWEYS-GluN2 Ab (p < 0.001), and eight cytokines (IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α-all p < 0.001-and IFN-γ, p = 0.026) than controls. Their cytokine levels did not differ from their mothers'; 23.9% of offspring met the criteria for a clinical psychiatric diagnosis. No differences were found in intelligence measures. Various neuropsychological scores correlated inversely with maternal psychophysical health. CONCLUSIONS: Offspring's profile suggests proinflammatory and autoimmune activation. Their rate of psychiatric diagnosis appears higher than in the general population, and their cognitive performance is related to maternal psychophysical health. Longitudinal research might investigate whether immunological and psychosocial conditions influence psychopathology and cognition. Graphical abstract The hypothesized sequence for physical and neuropsychological development for the SLE offspring.

Human-leukocyte antigen class II genes in early-onset obsessive-compulsive disorder.

Objective: The exact aetiology of obsessive-compulsive disorder (OCD) is unknown, although there is evidence to suggest a gene-environment interaction model. Several lines of evidence support a possible role of the immune system in this model. Methods: The present study explores the allele variability in HLA genes of class II (HLA-DRB1, HLA-DQB1) in a sample of 144 early-onset OCD compared with reference samples of general population in the same geographical area. Results: None of the 39 alleles identified (allele frequency >1%) showed significant differences between OCD and reference populations. Pooling the different alleles that comprised HLA-DR4 (including DRB1*04:01, DRB1*04:04 and DRB1*04:05 alleles) we observed a significantly higher frequency (X21 = 5.53, P = 0.018; OR = 1.64, 95% CI 1.08-2.48) of these alleles in the early-onset OCD sample (10.8%) than in the reference population (6.8%). Conclusions: Taking into account the role of HLA class II genes in the central nervous system, the results presented here support a role of the immune system in the pathophysiological model of OCD.

Genetic Associations of Serotoninergic and GABAergic Genes in an Extended Collection of Early-Onset Obsessive-Compulsive Disorder Trios.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder whose etiology includes important genetic contributions. In a previous transmission disequilibrium study in which 75 complete trios were included, single-nucleotide polymorphisms (SNPs) in serotoninergic and GABAergic genes were associated with early-onset OCD. Our aim was to assess those findings in an extended collection of early-onset OCD trios. METHODS: A transmission disequilibrium test for SNPs in HTR1B (rs2000292), SLC18A1 (rs6586896), GAD1 (rs3791860), and GAD2 (rs8190748) was performed in a total of 101 early-onset OCD trios, from which 26 trios were newly recruited for the purpose of the present analysis. RESULTS: All the SNPs were overtransmitted from parents to OCD probands (p < 0.012, significant after Bonferroni correction). CONCLUSIONS: These results are consistent with the previous findings and constitute more evidence of the role of genetic factors related to serotoninergic and GABAergic pathways in the pathophysiology of early-onset OCD.

European Multicentre Tics in Children Studies (EMTICS): protocol for two cohort studies to assess risk factors for tic onset and exacerbation in children and adolescents.

Genetic predisposition, autoimmunity and environmental factors [e.g. pre- and perinatal difficulties, Group A Streptococcal (GAS) and other infections, stress-inducing events] might interact to create a neurobiological vulnerability to the development of tics and associated behaviours. However, the existing evidence for this relies primarily on small prospective or larger retrospective population-based studies, and is therefore still inconclusive. This article describes the design and methodology of the EMTICS study, a longitudinal observational European multicentre study involving 16 clinical centres, with the following objectives: (1) to investigate the association of environmental factors (GAS exposure and psychosocial stress, primarily) with the onset and course of tics and/or obsessive-compulsive symptoms through the prospective observation of at-risk individuals (ONSET cohort: 260 children aged 3-10 years who are tic-free at study entry and have a first-degree relative with a chronic tic disorder) and affected individuals (COURSE cohort: 715 youth aged 3-16 years with a tic disorder); (2) to characterise the immune response to microbial antigens and the host's immune response regulation in association with onset and exacerbations of tics; (3) to increase knowledge of the human gene pathways influencing the pathogenesis of tic disorders; and (4) to develop prediction models for the risk of onset and exacerbations of tic disorders. The EMTICS study is, to our knowledge, the largest prospective cohort assessment of the contribution of different genetic and environmental factors to the risk of developing tics in putatively predisposed individuals and to the risk of exacerbating tics in young individuals with chronic tic disorders.