Indications of Linkage and Association of Gilles de la Tourette Syndrome in Two Independent Family Samples: 17q25 Is a Putative Susceptibility Region

Gilles de la Tourette syndrome (GTS) is characterized by multiple motor and phonic tics and high comorbidity rates with other neurobehavioral disorders. It is hypothesized that frontal-subcortical pathways and a complex genetic background are involved in the etiopathogenesis of the disorder. The genetic basis of GTS remains elusive. However, several genomic regions have been implicated. Among them, 17q25 appears to be of special interest, as suggested by various independent investigators. In the present study, we explored the possibility that 17q25 contributes to the genetic component of GTS. The initial scan of chromosome 17 performed on two large pedigrees provided a nonparametric LOD score of 2.41 near D17S928. Fine mapping with 17 additional microsatellite markers increased the peak to 2.61 (P=.002). The original families, as well as two additional pedigrees, were genotyped for 25 single-nucleotide polymorphisms (SNPs), with a focus on three genes in the indicated region that could play a role in the development of GTS, on the basis of their function and expression profile. Multiple three-marker haplotypes spanning all three genes studied provided highly significant association results (P<.001). An independent sample of 96 small families with one or two children affected with GTS was also studied. Of the 25 SNPs, 3 were associated with GTS at a statistically significant level. The transmission/disequilibrium test for a three-site haplotype moving window again provided multiple positive results. The background linkage disequilibrium (LD) of the region was studied in eight populations of European origin. A complicated pattern was revealed, with the pairwise tests producing unexpectedly high LD values at the telomeric TBCD gene. In conclusion, our findings warrant the further investigation of 17q25 as a candidate susceptibility region for GTS

Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained

A theoretical molecular network for dyslexia: integrating available genetic findings

Item does not contain fulltextDevelopmental dyslexia is a common specific childhood learning disorder with a strong heritable component. Previous studies using different genetic approaches have identified several genetic loci and candidate genes for dyslexia. In this article, we have integrated the current knowledge on 14 dyslexia candidate genes suggested by cytogenetic findings, linkage and association studies. We found that 10 of the 14 dyslexia candidate genes (ROBO1, KIAA0319, KIAA0319L, S100B, DOCK4, FMR1, DIP2A, GTF2I, DYX1C1 and DCDC2) fit into a theoretical molecular network involved in neuronal migration and neurite outgrowth. Based on this, we also propose three novel dyslexia candidate genes (SLIT2, HMGB1 and VAPA) from known linkage regions, and we discuss the possible involvement of genes emerging from the two reported genome-wide association studies for reading impairment-related phenotypes in the identified network

Integrated genome-wide association study findings: identification of a neurodevelopmental network for attention deficit hyperactivity disorder

Item does not contain fulltextOBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric disorder. In the present study, the authors investigated the presence of genomic convergence in the top findings of the five published genome-wide association studies (GWASs) of ADHD. METHOD: The authors carried out bioinformatics pathway analyses, using the Ingenuity and BiNGO tools, as well as a systematic literature analysis of 85 genes from the five published GWASs containing single nucleotide polymorphisms associated with ADHD at a p value <0.0001. RESULTS: Findings revealed that 45 of the 85 top-ranked ADHD candidate genes encode proteins that fit into a neurodevelopmental network involved in directed neurite outgrowth. Data on copy number variations in patients with ADHD and data from animal studies provide further support for the involvement of this network in ADHD etiology. Several network proteins are also directly modulated by stimulants, the most commonly used psychopharmacological treatment for ADHD. CONCLUSIONS: The authors have identified a protein network for ADHD that contributes to our understanding of the molecular basis of the disorder. In addition, the data suggest new candidate genes for ADHD and provide clues to future research into psychopharmacological ADHD treatments

The validity of DSM-IV-TR criteria B and C of hair-pulling disorder (trichotillomania): Evidence from a clinical study

In both DSM-IV-TR and the ICD-10, hair-pulling disorder (trichotillomania, or TTM) is described as hair-pulling, with a rising urge or tension prior to pulling or when attempting to resist, and pleasure, relief or gratification during or after pulling. However, it has been questioned whether all patients with hair-pulling experience these other phenomena, and whether they occur with all pulling episodes. The objective of this study was to examine the DSM-IV-TR requirement of criteria B and C for a diagnosis of TTM in a sample of people with hair-pulling. A multi-site sample of adults with hair-pulling who met both DSM-IV-TR diagnostic criteria B and C (n=82, 89.13%) were compared to those who failed to satisfy both B and C (n=10, 10.87%) on a number of clinical variables. There were no differences in hair-pulling severity, levels of comorbid depressive and anxiety symptoms, number of comorbid body-focused repetitive behaviors, or impairment between those patients who did and did not meet criteria B and C. Our study does not provide convincing support for the inclusion of the current diagnostic criteria B and C for TTM in DSM-5. © 2011 Elsevier Ireland Ltd.Articl

An integrated molecular landscape implicates the regulation of dendritic spine formation through insulin-related signalling in obsessive-compulsive disorder

BACKGROUND: Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with onset in childhood and is characterized by obsessions (recurrent, intrusive, persistent thoughts, impulses and/or ideas that often cause anxiety or distress) and compulsions (ritualized and stereotypic behaviours or mental acts that are often performed to relieve anxiety or distress associated with obsessions). Although OCD is a heritable disorder, its complex molecular etiology is poorly understood. METHODS: We combined enrichment analyses and an elaborate literature review of the top-ranked genes emerging from the 2 published genome-wide association studies of OCD and candidate genes implicated through other evidence in order to identify biological processes that, when dysregulated, increase the risk for OCD. RESULTS: The resulting molecular protein landscape was enriched for proteins involved in regulating postsynaptic dendritic spine formation - and hence synaptic plasticity - through insulin-dependent molecular signalling cascades. LIMITATIONS: This study is a first attempt to integrate molecuar information from different sources in order to identify biological mechanisms underlying OCD etiology. Our findings are constrained by the limited information from hypothesis-free studies and the incompleteness and existing limitations of the OCD literature and the gene function annotations of gene enrichment tools. As this study was solely based on in silico analyses, experimental validation of the provided hypotheses is warranted. CONCLUSION: Our work suggests a key role for insulin and insulin-related signalling in OCD etiology and - if confirmed by independent studies - could eventually pave the way for the development of novel OCD treatments

High sibling correlation on methylphenidate response but no association with DAT1-10R homozygosity in Dutch sibpairs with ADHD.

Contains fulltext : 47717.pdf (publisher's version ) (Closed access)BACKGROUND: A minority of patients with attention-deficit hyperactivity disorder (ADHD) do not respond favorably to methylphenidate. This has been partially associated with homozygosity for the Dopamine transporter (DAT1) 10-repeat allele and the presence of one or two Dopamine D4 receptor (DRD4) 7-repeat alleles. This study examined the sibling correlation of methylphenidate response rate and the possible association between response rate and these risk alleles. METHODS: A sample of 82 Dutch children with ADHD, from 54 families, (including 30 singletons and 28 sib pairs), who used methylphenidate, was phenotyped according to DSM-IV criteria. Patients were members of affected sib pairs and were genotyped for DAT1 and DRD4. The sibling Intraclass Correlation Coefficient for methylphenidate response rate was calculated. The association between individual response rates and the risk alleles was examined using linear regression techniques. RESULTS: The Intraclass Correlation Coefficient was significant (r=.563, p=.001). No evidence was found establishing an association between methylphenidate response and DAT1-homozygosity. There was a positive trend towards association with the presence of one or two DRD4-7R alleles. CONCLUSIONS: The sibling correlation may indicate a familial clustering of methylphenidate response. This response is possibly associated with the presence of one or two alleles at the DRD4-7R locus, but not with DAT1-10R homozygosity in the Dutch population