Abstract Background Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease ...pathogenesis. In a previous small-scale copy number variation study of a GTS cohort ( n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase ( AADAC ), were observed and merited further investigations. Methods We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC , identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues. Results In the Danish cohort, we identified eight patients with overlapping deletions of AADAC . Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association ( p = 4.4 × 10−4 ; odds ratio = 1.9; 95% confidence interval = 1.33–2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology. Conclusions AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.
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. Ann Neurol 2014;76:310–315
Epigenome-Wide Association Study of Tic Disorders Zilhão, Nuno R; Padmanabhuni, Shanmukha S; Pagliaroli, Luca ...
Twin research and human genetics,
12/2015, Letnik:
18, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Tic disorders are moderately heritable common psychiatric disorders that can be highly troubling, both in childhood and in adulthood. In this study, we report results obtained in the first ...epigenome-wide association study (EWAS) of tic disorders. The subjects are participants in surveys at the Netherlands Twin Register (NTR) and the NTR biobank project. Tic disorders were measured with a self-report version of the Yale Global Tic Severity Scale Abbreviated version (YGTSS-ABBR), included in the 8th wave NTR data collection (2008). DNA methylation data consisted of 411,169 autosomal methylation sites assessed by the Illumina Infinium HumanMethylation450 BeadChip Kit (HM450k array). Phenotype and DNA methylation data were available in 1,678 subjects (mean age = 41.5). No probes reached genome-wide significance (p < 1.2 × 10(-7)). The strongest associated probe was cg15583738, located in an intergenic region on chromosome 8 (p = 1.98 × 10(-6)). Several of the top ranking probes (p < 1 × 10(-4)) were in or nearby genes previously associated with neurological disorders (e.g., GABBRI, BLM, and ADAM10), warranting their further investigation in relation to tic disorders. The top significantly enriched gene ontology (GO) terms among higher ranking methylation sites included anatomical structure morphogenesis (GO:0009653, p = 4.6 × 10-(15)) developmental process (GO:0032502, p = 2.96 × 10(-12)), and cellular developmental process (GO:0048869, p = 1.96 × 10(-12)). Overall, these results provide a first insight into the epigenetic mechanisms of tic disorders. This first study assesses the role of DNA methylation in tic disorders, and it lays the foundations for future work aiming to unravel the biological mechanisms underlying the architecture of this disorder.
Abstract Background Childhood trauma exposure (CTE) is frequently reported by those with substance use disorders (SUDs). SUDs also frequently co-occur with attention deficit hyperactivity disorder ...(ADHD). Objective To investigate the role of childhood trauma exposure (CTE) in the presence and the persistence of ADHD in treatment seeking SUD patients. Method Data was derived from the International ADHD in Substance Use Disorder Prevalence (IASP) study. A structured interview was administered to 1
274 treatment-seeking SUD patients aged 18 to 65. Results CTE was present in 53.5% of the patients and comorbid adult ADHD in 14.1%. CTE was significantly associated with ADHD: the prevalence of adult ADHD with and without CTE was 19.4% and 8.5% (OR adjusted for age, gender, main substance of abuse, BPD, and ASPD 1.91 95% CI 1.29
–
2.81). CTE was not associated with the severity of adult ADHD or with the persistence of childhood ADHD into adulthood. Conclusions CTE is common in SUD patients and associated with adult ADHD but not with the persistence of childhood ADHD into adulthood. These findings suggest that the increased rate of adult ADHD in SUD patients with CTE is not the consequence of a negative effect of CTE on the persistence of childhood ADHD into adulthood, but a direct expression of the high rate of childhood ADHD in SUD patients with CTE.
Candidate genes of the dopaminergic system have been reported as key elements in shaping human temperament. Catechol-O-methyltransferase (COMT) plays a vital role in dopamine inactivation, and the ...Val(158)Met single nucleotide polymorphism (rs4680) in its gene has been recently associated with the Novelty Seeking (NS) temperament scale of the Temperament and Character Inventory in studies of healthy adults, as well as methamphetamine abusers.
Our goal was to examine the association between temperament dimensions of the Temperament and Character Inventory and the COMT Val(158)Met variation in a Hungarian sample of 117 heroin-dependent patients and 124 nondependent controls.
Case-control analysis did not show any significant difference in allele or genotype distributions. However, dimensional approach revealed an association between the COMT Val(158)Met and NS (P = .01): both controls and opiate users with Met/Met genotypes showed higher NS scores compared to those with the Val allele. The NS scores are also significantly higher among opiate users; however, no interaction was found between group status and COMT genotype.
Association of the COMT polymorphism and NS temperament scale has been shown for heroin-dependent patients and controls regardless of group status.
This study aims to assess the validity of the ADHD module of the Mini-International Neuropsychiatric Interview (MINI-Plus) in patients with substance use disorders (SUD), using the Conners’ Adult ...ADHD Diagnostic Interview for DSM-IV (CAADID) as the external criterion.
A cross sectional international multi-center study in 10 countries was conducted in treatment seeking SUD patients. A sample of 1263 patients with both MINI-Plus and CAADID was analyzed to determine the psychometric properties of the MINI-Plus.
According to the CAADID, 179 patients (14.2%) met criteria for adult ADHD, whereas according to the MINI-Plus 227 patients (18.0%) were identified as having adult ADHD. Sensitivity of the MINI-Plus ADHD module was 74%, specificity was 91%, positive predictive value was 60% and negative predictive value was 96%. Kappa was 0.60.
The MINI-Plus has acceptable criterion validity for the screening of adult ADHD in treatment seeking SUD patients.
On the basis of the results, The MINI-Plus may be used for the screening of ADHD in SUD patients.
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