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Abstract

Different analytic strategies, including linkage, association and meta-analysis support a role of CDH13 in the susceptibility to attention deficit/hyperactivity disorder (ADHD). CDH13 codes for cadherin 13 (or H-cadherin), which is a member of a family of calcium-dependent cell-cell adhesion proteins and a regulator of neural cell growth. We tested the association between CDH13 on three executive functioning tasks that are promising endophenotypes of ADHD. An adjusted linear regression analysis was performed in 190 ADHD-affected Dutch probands of the IMAGE project. Three executive functions were examined: inhibition, verbal and visuo-spatial working memory (WM). We tested 2632 single nucleotide polymorphisms (SNPs) within CDH13 and 20 kb up- and downstream of the gene (capturing regulatory sequences). To adjust for multiple testing within the gene, we applied stringent permutation steps. Intronic SNP rs11150556 is associated with performance on the Verbal WM task. No other SNP showed gene-wide significance with any of the analyzed traits, but a 72-kb SNP block located 446 kb upstream of SNP rs111500556 showed suggestive evidence for association (P-value range 1.20E-03 to 1.73E-04) with performance in the same Verbal WM task. This study is the first to examine CDH13 and neurocognitive functioning. The mechanisms underlying the associations between CDH13 and the clinical phenotype of ADHD and verbal WM are still unknown. As such, our study may be viewed as exploratory, with the results presented providing interesting hypotheses for further testing.

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... Arias-Vasquez et al. (2011) showed an association of a SNP in intron 6 with verbal working memory measurements in a case-control sample on a gene-wide level. Furthermore, there was a 72 kb haploblock only 12 kb upstream of rs2199430 with suggestive, though not gene-wide significant, association with verbal memory [26]. This study is the only one that has specifically addressed cognitive endophenotypes in ADHD related to CDH13 variation in humans so far. ...
... It is unknown whether and how this is reflected by the functional integrity of neural circuitry in humans. Preliminary evidence points to the effect of CDH13 on personality traits [23] and executive functions [19,26], but no study has searched for an association of CDH13 with these dimensional endophenotypes in adult ADHD patients. Therefore, we investigated the effect of functional CDH13 SNP rs2199430 in aADHD on various levels to challenge the hypothesis that common SNP variation in CDH13 is associated with ADHD beyond the categorical syndrome. ...
... Quality control of microarray raw data was performed according to the Ricopili pipeline (https://sites.google.com/a/broadinstitute.org/ricopili/, accessed on 26 August 2021), excluding SNPs with call rate (CR) < 99%, MAF < 1% and SNPs that deviate from HWE (p < 1 × 10 −10 ) as well as individuals with CR < 95%, outlier from principal component analyses (>3-fold SD from PC1-PC3), gender discrepancies and related or duplicated individuals. To ensure accordance with the genotyping results of our PCR method and the chip array data, 50 samples with available chip data were additionally genotyped by PCR with a 100% match of genotyping results. ...
... Arias-Vasquez et al. (2011) showed an association of a SNP in intron 6 with verbal working memory measurements in a case-control sample on a gene-wide level. Furthermore, there was a 72 kb haploblock only 12 kb upstream of rs2199430 with suggestive, though not gene-wide significant, association with verbal memory [26]. This study is the only one that has specifically addressed cognitive endophenotypes in ADHD related to CDH13 variation in humans so far. ...
... It is unknown whether and how this is reflected by the functional integrity of neural circuitry in humans. Preliminary evidence points to the effect of CDH13 on personality traits [23] and executive functions [19,26], but no study has searched for an association of CDH13 with these dimensional endophenotypes in adult ADHD patients. Therefore, we investigated the effect of functional CDH13 SNP rs2199430 in aADHD on various levels to challenge the hypothesis that common SNP variation in CDH13 is associated with ADHD beyond the categorical syndrome. ...
... Quality control of microarray raw data was performed according to the Ricopili pipeline (https://sites.google.com/a/broadinstitute.org/ricopili/, accessed on 26 August 2021), excluding SNPs with call rate (CR) < 99%, MAF < 1% and SNPs that deviate from HWE (p < 1 × 10 −10 ) as well as individuals with CR < 95%, outlier from principal component analyses (>3-fold SD from PC1-PC3), gender discrepancies and related or duplicated individuals. To ensure accordance with the genotyping results of our PCR method and the chip array data, 50 samples with available chip data were additionally genotyped by PCR with a 100% match of genotyping results. ...
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The cell–cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The Rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
... Thus far, more than 20 studies have found associations between CDH13 and attention deficit/hyperactivity disorder (ADHD), autism, schizophrenia, substance abuse or bipolar disorder. [23][24][25][26][27][28][29][30][31][32][33] CDH13 was identified as a ADHD-related gene in 2008, and it is one of the most important genes associated with ADHD, 26 which is a disorder strongly associated with violent criminality. 34,35 Our best hit, the rs11649622 genotype, has been observed to be linked to CDH13 expression especially in amygdala, 36 and other CDH13 variants have been observed to be associated with working memory 24 and cortical thickness in dorsolateral prefrontal cortex of patients with ADHD. ...
... [23][24][25][26][27][28][29][30][31][32][33] CDH13 was identified as a ADHD-related gene in 2008, and it is one of the most important genes associated with ADHD, 26 which is a disorder strongly associated with violent criminality. 34,35 Our best hit, the rs11649622 genotype, has been observed to be linked to CDH13 expression especially in amygdala, 36 and other CDH13 variants have been observed to be associated with working memory 24 and cortical thickness in dorsolateral prefrontal cortex of patients with ADHD. 37 CDH13 codes for T-cadherin, a GPI-anchored protein, which has an important role in the proliferation, migration and connectivity of neurons, 30,32 and disturbed neural connectivity has been proposed as the main pathophysiological mechanism underlying behavioral problems in ADHD. ...
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In developed countries, the majority of all violent crime is committed by a small group of antisocial recidivistic offenders, but no genes have been shown to contribute to recidivistic violent offending or severe violent behavior, such as homicide. Our results, from two independent cohorts of Finnish prisoners, revealed that a monoamine oxidase A (MAOA) low-activity genotype (contributing to low dopamine turnover rate) as well as the CDH13 gene (coding for neuronal membrane adhesion protein) are associated with extremely violent behavior (at least 10 committed homicides, attempted homicides or batteries). No substantial signal was observed for either MAOA or CDH13 among non-violent offenders, indicating that findings were specific for violent offending, and not largely attributable to substance abuse or antisocial personality disorder. These results indicate both low monoamine metabolism and neuronal membrane dysfunction as plausible factors in the etiology of extreme criminal violent behavior, and imply that at least about 5-10% of all severe violent crime in Finland is attributable to the aforementioned MAOA and CDH13 genotypes.Molecular Psychiatry advance online publication, 28 October 2014; doi:10.1038/mp.2014.130.
... The rs11150556 polymorphism was associated with verbal workingmemory (VWM) performance in children with ADHD. Carriers of the CC genotype showed a significant worse performance when compared to CT and TT carriers [Arias-Vásquez et al., 2011]. The second study aimed to identify, characterize and estimate coding CDH13 variants in adults with ADHD [Mavroconstanti et al., 2013]. ...
... Three SNPS (CDH13 rs11646411, rs6565113) and CTNNA2 rs13395022) were chosen because they are GWAS top hits [Poelmans et al., 2011]. CDH13 rs11150556 was included due to its association with verbal working-memory in children with ADHD [Arias-Vásquez et al., 2011]. ...
Article
Several efforts have been made to find new genetic risk variants which explain the high heritability of ADHD. At the genome level, genes involved in neurodevelopmental pathways were pointed as candidates. CDH13 and CTNNA2 genes are within GWAS top hits in ADHD and there are emerging notions about their contribution to ADHD pathophysiology. The main goal of this study is to test the association between SNPs in CDH13 and CTNNA2 genes and ADHD across the life cycle in subjects with ADHD. This study included 1,136 unrelated ADHD cases and 946 individuals without ADHD. No significant association between CDH13 and CTNNA2 was observed between cases and controls across different samples (P ≥ 0.096 for all comparisons). No allele was significantly more transmitted than expected from parents to ADHD probands. The CDH13 rs11150556 CC genotype was associated with more hyperactive/impulsive symptoms in youths with ADHD (children/adolescents clinical sample: F = 7.666, P = 0.006, FDR P-value = 0.032; Pelotas Birth Cohort sample: F = 6.711, P = 0.011, FDR P-value = 0.032). Although there are many open questions regarding the role of neurodevelopmental genes in ADHD symptoms, the present study suggests that CDH13 is associated with hyperactive/impulsive symptoms in youths with ADHD. © 2014 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
... The protein produced by CDH13 acts as a negative regulator of axon growth during neural differentiation (Takeuchi et al. 2000) and is expressed in various regions of the brain implicated in drug reward Zhong et al. 2015), which could impact neuropharmacological phenotypes that alter response to psychostimulants. In addition to the findings involving rs3784943 in the abovementioned GWAS (Hart et al. 2012), other variants in the CDH13 have been demonstrated to be associated with methamphetamine dependence, cigarette smoking, and various psychiatric phenotypes (Adkins et al. 2011;Arias-Vásquez et al. 2011;Drgon et al. 2009;Rivero et al. 2013;Terracciano et al. 2010;Thorgeirsson et al. 2010;Uhl et al. 2008;Uhl et al. 2007). ...
... While some research suggests that genetic moderators of d-amphetamine effects may be detected mainly at lower doses (Hart et al. 2012;Veenstra-VanderWeele et al. 2006), other studies suggest that genetic differences in amphetamine response may be dose-dependent (Lott et al. 2006). While only one SNP was genotyped in the current sample, CDH13 is a fairly large gene and its other SNPs have associated with other relevant behavioral phenotypes (Adkins et al. 2011;Arias-Vásquez et al. 2011;Drgon et al. 2009;Rivero et al. 2013;Terracciano et al. 2010;Thorgeirsson et al. 2010;Uhl et al. 2008;Uhl et al. 2007). Hence, it is unknown whether the rs3784943 SNP is in linkage disequilibrium with several other SNPs of interest, which should be addressed in future work. ...
Article
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RationaleA previous genome-wide association study (GWAS) in a predominately Caucasian sample of healthy young adults linked greater amphetamine-induced rewarding effects with the rs3784943 G allele of the cadherin 13 (CDH13; i.e., a cell adhesion molecule implicated in neuronal connectivity) gene. This association has not been subsequently examined, nor has it been studied in Asian populations, which may have greater frequencies of the risk allele. Objective The objective of this study was to examine the association of rs3784943 with amphetamine response in a racially heterogeneous sample (37 % Asian) of healthy young adults. Methods Participants (N = 84; 18–35 years old) genotyped for rs3784943 completed counterbalanced sessions involving 20 mg oral d-amphetamine or placebo administration. At both sessions, cardiovascular and subjective drug effects measures were collected. ResultsIn the combined racially heterogeneous sample, amphetamine (vs. placebo) effects were significantly greater on “Feel Drug” ratings (p < 0.05) and marginally greater on “Feel High” ratings and systolic blood pressure (p < 0.10) in G/A + G/G genotypes than A/A genotypes. The G allele was more common among Asian than other racial groups. Among the subsample of Asian participants (N = 31), drug effects were significantly greater on Feel Drug (p < 0.05) and marginally greater on Feel High and heart rate (p < 0.10) among Asians with G/A + G/G (vs. A/A) genotypes. Conclusions In concert with a previous GWAS result, this candidate gene study provides convergent evidence implicating CDH13 rs3784943 variant in d-amphetamine’s drug effect profile and suggests generalization to Asian populations. CDH13 and genes coding for other cell adhesion molecules may be worthy of study in the biology of psychostimulant abuse liability.
... Evidence for an involvement of CDH13 was revealed by several GWAS associating this gene with ADHD (Lesch et al., 2008;Neale et al., 2010; for a review, see Rivero et al., 2013) and ASD (Sanders et al., 2011). Other studies have associated CDH13 with the performance of working memory in ADHD (Arias-V asquez et al., 2011). Overall, variants of CDH13 have been suggested to exert a modest effect, with mild to subclinical consequences, but capable of impacting the overall genetic burden if interacting with other risk factors. ...
Article
Background and scope: Neurodevelopmental disorders (NDDs) are defined by a wide variety of behavioural phenotypes, psychopathology and clinically informed categorical classifications. Diagnostic entities include intellectual disability (ID), the autism spectrum (ASD) and attention-deficit/hyperactivity disorder (ADHD). The aetiopathogenesis of these conditions and disorders involves an interaction between both genetic and environmental risk factors on the developmental trajectory. Despite their remarkable genetic heterogeneity and complexity of pathophysiological mechanisms, NDDs display an overlap in their phenotypic features, a considerable degree of comorbidity as well as sharing of genetic and environmental risk factors. This review aims to provide an overview of the genetics and epigenetic of NDDs. Findings: Recent evidence suggests a critical role of defined and tightly regulated neurodevelopmental programs running out of control in NDDs, most notably neuronal proliferation and migration, synapse formation and remodelling, as well as neural network configuration resulting in compromised systems connectivity and function. Moreover, the machinery of epigenetic programming, interacting with genetic liability, impacts many of those processes and pathways, thus modifying vulnerability of, and resilience to, NDDs. Consequently, the categorically defined entities of ID, ADHD and ASD are increasingly viewed as disorders on a multidimensional continuum of molecular and cellular deficiencies in neurodevelopment. As such, this range of NDDs displays a broad phenotypic diversity, which may be explained by a combination and interplay of underlying loss- and potential gain-of-function traits. Conclusion: In this overview, we discuss a backbone continuum concept of NDDs by summarizing pertinent findings in genetics and epigenetics. We also provide an appraisal of the genetic overlap versus differences, with a focus on genome-wide screening approaches for (epi)genetic variation. Finally, we conclude with insights from evolutionary psychobiology suggesting positive selection for discrete NDD-associated traits.
... The empirical p value can be achieved by comparing the obtained test statistic to all the other test statistics across all data divisions forming the null distribution. Several articles in this review adopted PTs for multiple comparison on gene and behavior research (e.g., Arias-Vasquez et al., 2011;Lerer et al., 2010;Liao et al., 2009). ...
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Over the past two decades, permutation tests (PTs) have received much attention in the educational and behavioral sciences. The aim of this article is to review the theoretical developments of PTs, the active areas in the educational and behavioral research using PTs, and the types of analysis under which PTs have been applied. We obtained 224 published articles, which included 141 theoretical articles and 83 application articles. After scrutinizing each article, we are happy to see that (1) some researchers began to advocate introducing PTs into basic statistics training; (2) computing load for PTs may be reduced dramatically by some intelligent algorithms; (3) PTs began to be applied in new areas such as studies on the relationship between brain and behavior and the relationship between gene and behavior; (4) besides simple types of analysis such as independent two-group comparison, PTs can also be carried out under more complex situations such as multivariate analysis. However, we should also notice that PTs are still mostly used for simple analyses (e.g., randomness analysis). (PsycINFO Database Record (c) 2014 APA, all rights reserved)
... However, CDH13 still continues to be one of the most relevant genes on ADHD and related comorbid conditions. Recently, the association between CDH13 and executive function tasks as endophenotypes of ADHD was tested and a significant link between SNP rs11150556 and verbal working memory performance was found (Arias-Vasquez et al., 2011). Similarly, the CDH13 SNP rs11150556 CC genotype was identified as being significantly associated with hyperactive/impulsive symptoms in adolescents with ADHD (Salatino-Oliveira et al., 2015). ...
Thesis
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter involved in early developmental processes such as cell proliferation, migration, and differentiation. Recent research in humans showed that the brain 5-HT system and CDH13 are interlinked in the genetics of neurodevelopmental disorders including attention- deficit/hyperactivity disorder and autism spectrum disorder (Lesch et al., 2008; Neale et al., 2008; Neale, Medland, Ripke, Anney, et al., 2010; Neale, Medland, Ripke, Asherson, et al., 2010; Sanders et al., 2011; Sanders et al., 2015; Zhou et al., 2008). This study introduces Cadherin-13 (CDH13), a cell adhesion protein, as a contributor to the development and function of the 5-HT system. Our experiments show that the absence of CDH13 increases the density of 5-HT neurons in the developing dorsal raphe (DR) and increases the 5-HT innervation of the prefrontal cortex in mouse embryonic stages. CDH13 is also observed in radial glial cells, an important progenitor cell type linked to neuronal migration. A three-dimensional reconstruction carried out with super-resolution microscopy, identifies 5-HT neurons intertwined with radial glial cells, and CDH13 clusters at contact points between these cells. This indicates a potential contribution of CDH13 to the migration of DR 5-HT neurons. As CDH13 is strongly expressed in 5-HT neurons, we asked whether the selective deletion of CDH13 from these cells is sufficient to generate the alterations observed in the Cdh13 constitutive knockout mouse line. In 5-HT conditional Cdh13 knockout mice (Cdh13 cKO) an increase in DR 5-HT neurons in the embryonic and adult brains is observed, as well as 5-HT hyperinnervation of cortical regions. Therefore, illustrating that the lack of CDH13 from 5-HT neurons alone impacts DR formation and serotonergic innervation. Behavioral testing conducted on Cdh13 cKO mice showed delayed learning in visuospatial learning and memory processing, as well as, changes in sociability parameters. To find out how CDH13 localizes in human 5-HT neurons, CDH13 was visualized in neurons that derived from human induced pluripotent stem cells (iPSC). Super-resolution microscopy confirmed CDH13 expression in a subgroup of induced human neurons positive for typical hallmarks of 5-HT neurons, such as expression of Tph2, the neuron-specific tryptophan hydroxylase, and synaptic structures. In summary, the work included in this thesis presents a detailed analysis of CDH13 expression and localization in the 5-HT system and shows that deletion of CDH13 from 5-HT neurons affects specific higher-order functions of the brain.
... Several previous studies have examined the utility of quantitative phenotypes in genetic linkage studies of ADHD, and some have examined a wide range of neurocognitive phenotypes [Cho, 2008;Doyle, 2008;Johnson, 2008;Rommelse et al., 2008b;Goos, 2009;Konrad, 2010;Arias-Vasquez, 2011;Pineda, 2011]. One study of particular relevance to our work examined the heritability of a variety of cognitive measures in a population isolate that is genetically closely related to our CVCR population (the region of Antioquia, Colombia) [Pineda, 2011]. ...
Article
Attention deficit hyperactivity disorder (ADHD) is associated with substantial functional impairment in children and in adults. Many individuals with ADHD have clear neurocognitive deficits, including problems with visual attention, processing speed, and set shifting. ADHD is etiologically complex, and although genetic factors play a role in its development, much of the genetic contribution to ADHD remains unidentified. We conducted clinical and neuropsychological assessments of 294 individuals (269 with ADHD) from 163 families (48 multigenerational families created using genealogical reconstruction, 78 affected sib pair families, and 37 trios) from the Central Valley of Costa Rica (CVCR). We used principal components analysis (PCA) to group neurocognitive and behavioral variables using the subscales of the Child Behavior Checklist (CBCL) and 15 neuropsychological measures, and created quantitative traits for heritability analyses. We identified seven cognitive and two behavioral domains. Individuals with ADHD were significantly more impaired than their unaffected siblings on most behavioral and cognitive domains. The verbal IQ domain had the highest heritability (92%), followed by auditory attention (87%), visual processing speed and problem solving (85%), and externalizing symptoms (81%). The quantitative traits identified here have high heritabilities, similar to the reported heritability of ADHD (70-90%), and may represent appropriate alternative phenotypes for genetic studies. The use of multigenerational families from a genetically isolated population may facilitate the identification of ADHD risk genes in the face of phenotypic and genetic heterogeneity. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
... 105 Second, in a cohort of 238 children, the presence of the ADHD-associated SNP in cadherin-13 was found to specifically correlate with a defect in verbal working memory, but not with spatial working memory. 106 This finding provides the first glimpse that cadherins may also regulate circuit specificity in humans. It suggests that cadherin-13 may be required for the formation of specific circuits involved with verbal working memory but not for circuits specific to spatial working memory or other cognitive functions. ...
Article
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During brain development, billions of neurons organize into highly specific circuits. To form specific circuits, neurons must build the appropriate types of synapses with appropriate types of synaptic partners while avoiding incorrect partners in a dense cellular environment. Defining the cellular and molecular rules that govern specific circuit formation has significant scientific and clinical relevance because fine scale connectivity defects are thought to underlie many cognitive and psychiatric disorders. Organizing specific neural circuits is an enormously complicated developmental process that requires the concerted action of many molecules, neural activity, and temporal events. This review focuses on one class of molecules postulated to play an important role in target selection and specific synapse formation: the classic cadherins. Cadherins have a well-established role in epithelial cell adhesion, and although it has long been appreciated that most cadherins are expressed in the brain, their role in synaptic specificity is just beginning to be unraveled. Here, we review past and present studies implicating cadherins as active participants in the formation, function, and dysfunction of specific neural circuits and pose some of the major remaining questions.
... (3) Cell adhesion. CDH13 is involved in memory formation and development of brain networks [68,69]. KIRREL3 encodes putative cell adhesion molecules which is involved in synapse formation and neurogenesis [70]. ...
Article
Meta-analysis of data from genome-wide association studies (GWAS) of Alzheimer's disease (AD) has confirmed the high risk of APOE and identified twenty other risk genes/loci with moderate effect size. However, many more risk genes/loci remain to be discovered to account for the missing heritability. The contributions from individual singe-nucleotide polymorphisms (SNPs) have been thoroughly examined in traditional GWAS data analysis, while SNP-SNP interactions can be explored by a variety of alternative approaches. Here we applied generalized multifactor dimensionality reduction to the re-analysis of four publicly available GWAS datasets for AD. When considering 4-order intragenic SNP interactions, we observed high consistency of discovered potential risk genes among the four independent GWAS datasets. Ten potential risk genes were observed across all four datasets, including PDE1A, RYR3, TEK, SLC25A21, LOC729852, KIRREL3, PTPN5, FSHR, PARK2, and NR3C2. These potential risk genes discovered by generalized multifactor dimensionality reduction are highly relevant to AD pathogenesis based on multiple layers of evidence. The genetic contributions of these genes warrant further confirmation in other independent GWAS datasets for AD.
... In a review of five genome-wide association studies, Franke et al. (2009) noted that, whereas few of the 'classic' candidate genes, such as DAT4 a dopamine transporter gene, showed a reliable association with ADHD, the cell adhesion molecule cadherin CDH13 was the most common associate among the studies (also see Banaschewski et al., 2010). CDH13 is associated with many of the symptoms of ADHD (Mick et al., 2011), and with impaired working memory (Arias-Vásquez et al., 2011). CDH13 plays many roles in the brain (Rivero et al., 2012), among them a negative growth regulator for astrocytes (Huang et al., 2003). ...
Article
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Boakes, Patterson, Kendig, and Harris (2015) showed that schedule-induced drinking (SID), typically concentrated in the first half of the interpellet interval, is not moved there exclusively by competition from magazine entries, and that not all arbitrary responses can be maintained by adventitious reinforcement. They attribute such inferences to Killeen and Pellón (2013) and Patterson and Boakes (2012), and on that basis reject their explanation for the excessive nature of many adjunctive responses as a result of reinforcement. It is a mistaken attribution, as Killeen and Pellón emphasized that reinforcers act on many competing interim and terminal responses. That attribution is a minor oversight on the authors' part; their return to a discredited motivational account is, however, a major blunder. It discards the seminal recent advances in understanding the nature of schedule-induced responses (e.g., those of Patterson and Boakes), and even the positive contributions of their own article: Their data show very strong correlations between magazine entries and drinking, providing much more evidence for response competition than their microanalysis provides against it. (PsycINFO Database Record
... 35,36 Various approaches, including linkage analysis and association studies, have indicated various candidate genes, such as ROBO1 or CHD13, associated with low WM performances as a specific endophenotype of a cognitive dysfunction. 37,38 Remediation of these types of LDs can often be more effectively achieved when the precise cognitive dysfunction has been identified. 35 Currently, the functional roles of genes that have been identified in cognitive disorders can be separated into two main functional groups 39 : (i) neuronal differentiation and specification; and (ii) synaptic scaffolding and functioning. ...
Article
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Learning disabilities (LDs) are a clinically and genetically heterogeneous group of diseases. Array-CGH and high-throughput sequencing have dramatically expanded the number of genes implicated in isolated intellectual disabilities and LDs, highlighting the implication of neuron-specific post-mitotic transcription factors and synaptic proteins as candidate genes. We report a unique family diagnosed with autosomal dominant learning disability and a 6p21 microdeletion segregating in three patients. The 870 kb microdeletion encompassed the brain-expressed gene LRFN2, which encodes for a synaptic cell adhesion molecule. Neuropsychological assessment identified selective working memory deficits, with borderline intellectual functioning. Further investigations identified a defect in executive function, and auditory-verbal processes. These data were consistent with brain MRI and FDG-PET functional brain imaging, which, when compared with controls, revealed abnormal brain volume and hypometabolism of gray matter structures implicated in working memory. We performed electron microscopy immunogold labeling demonstrating the localization of LRFN2 at synapses of cerebellar and hippocampal rat neurons, often associated with the NR1 subunit of N-methyl-D-aspartate receptors (NMDARs). Altogether, the combined approaches imply a role for LRFN2 in LD, specifically for working memory processes and executive function. In conclusion, the identification of familial cases of clinically homogeneous endophenotypes of LD might help in both the management of patients and genetic counseling for families.European Journal of Human Genetics advance online publication, 21 October 2015; doi:10.1038/ejhg.2015.221.
... By altering the kinetics and sensitivity of this receptor, the differential methylation within Kctd16 and Gaba b may therefore contribute to the modulation of cocaine seeking behavior. CDH13 is a particularly striking candidate, as polymorphisms within this gene have been implicated in substance dependence (Uhl et al., 2008), vulnerability to addiction (Johnson et al., 2011), and disorders of impulse control (Arias-Vasquez et al., 2011), although no studies have explored the epigenetic regulation of this gene in cocaine seeking and addiction. Polymorphisms within Mctp1 are associated with bipolar disorder (Scott et al., 2009), and the expression of Mctp1 is altered during abstinence from several drugs of abuse (Le Merrer et al., 2012), though the cellular changes that give rise to this alteration remain to be determined. ...
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Continued vulnerability to relapse during abstinence is characteristic of cocaine addiction and suggests that drug-induced neuroadaptations persist during abstinence. However, the precise cellular and molecular attributes of these adaptations remain equivocal. One possibility is that cocaine self-administration leads to enduring changes in DNA methylation. To address this possibility, we isolated neurons from medial prefrontal cortex and performed high throughput DNA sequencing to examine changes in DNA methylation following cocaine self-administration. Twenty-nine genomic regions became persistently differentially methylated during cocaine self-administration, and an additional 28 regions became selectively differentially methylated during abstinence. Altered DNA methylation was associated with isoform-specific changes in the expression of co-localizing genes. These results provide the first neuron-specific, genome-wide profile of changes in DNA methylation induced by cocaine self-administration and protracted abstinence. Moreover, our findings suggest that altered DNA methylation facilitates long-term behavioral adaptation in a manner that extends beyond the perpetuation of altered transcriptional states.
... Notably, in several independent studies, CDH13 has been associated with the risk for attentiondeficit/hyperactivity disorder (ADHD) and frequent comorbid conditions including drug and alcohol abuse. [4][5][6][7][8][9][10][11][12][13][14][15][16][17] In addition, CDH13 was implicated in depression, 7,18 autism spectrum disorders, 19 schizophrenia 20 and bipolar disorder. 21 Variations in CDH13 have also been associated with the personality trait of extraversion 22 and extremely violent behavior. ...
Article
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Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo)phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13−/− mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13−/− mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism.
... The first study observed an association between this gene and performance on a verbal working memory test in a sample of ADHD children. [37] More recently, an association between CDH13 and hyperactive-impulsive symptoms in youths but not adults with ADHD was reported. [38] The most recent GWASs on childhood ADHD report some overlap with findings from previous studies. ...
Article
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder affecting children, adolescents, and adults. The prevalence is estimated at 5 to 7% of school-aged children and 2.5 to 5% of adults. The phenotype is complex and heterogeneous, presenting variable clinical features, developmental course, and outcome. The genetic susceptibility to ADHD is attributed to both common and rare variants from a broad range of genes related mainly to neurotransmission and neurodevelopment pathways. However, it has been difficult to identify the genetic risk variants that account for the high heritability of this disorder. In this paper, we present recent findings from molecular genetics studies on both child and adult ADHD. Challenges and future directions for ADHD genetic studies are reviewed and discussed.
... CDH13 encodes cadherin-13, a calcium-dependent protein important in cell-cell adhesion and neural cell growth, expressed in the cerebral cortex . Moreover, single nucleotide polymorphisms within CDH13 have been linked to working memory deficits and hyperactivity/impulsivity in ADHD individuals (Arias-Vásquez et al. 2011, Salatino-Oliveira et al. 2015. GFOD1 is a gene expressed in the brain and involved in electron transport, but its implications for ADHD are less known ). ...
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Attention deficit/hyperactivity disorder (ADHD) is one of the most commonly diagnosed developmental disorders in childhood characterized by hyperactivity, impulsivity and inattention. ADHD manifests in the child’s development by deficits in cognitive, executive and perceptor-motor functions, emotional regulation and social adaptation. Although the exact cause has not yet been known, the crucial role in the development of this disease plays the interaction of genetic, neurobiological and epigenetic factors. According to current knowledge, ADHD is defined as a biological dysfunction of central nervous system with genetically or organically defined deficits in noradrenergic and dopaminergic neurotransmission associated with structural abnormalities, especially in prefronto-striatal regions. In this context, a significant part of the difficulties could be due to a faulty control of fronto-striato-thalamo-cortical circuits important for attention, arousal and executive functions. Moreover, ADHD is associated with abnormal autonomic regulation. Specifically, reduced cardiac-linked parasympathetic activity associated with relative sympathetic dominance indexed by low heart rate variability can represent a noninvasive marker for prefrontal hypoactivity. However, the mechanisms underlying altered autonomic regulation in ADHD are still unknown. In this aspect, the evaluation of central autonomic regulation by noninvasive methods, namely pupillometry and eye-tracking, may provide novel information for better understanding of the neurobiological pathomechanisms leading to ADHD.
... The differences in locomotion that we identify here display interactions with gender that are reminiscent of the influences of gender on ADHD diagnoses and/or symptomatology. CDH13 associations with cognitive function in children with ADHD or autism fit nicely with the influences of Cdh13 variation on task acquisition that we note here (46)(47)(48). We failed to identify any significant influences of Cdh13 variation on the sorts of impulsivity measured by 5 choice serial reaction time testing (49), although this "impulsivity" indicator may not assess all forms of impulsivity present in human disorders. ...
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The cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered Cdh13 expression as models for common human variation at this locus. Constitutive cdh13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine conditioned taste aversion. Reduced adult Cdh13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical Cdh13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly-quicker acquisition of rotarod and water maze tasks, with a trend toward faster acquisition of 5 choice serial reaction time tasks that otherwise displayed no genotype-related differences. They display significant differences in locomotion in some settings, with larger effects in males. In assessments of brain changes that might contribute to these behavioral differences, there are selective alterations of dopamine levels, dopamine/metabolite ratios, dopaminergic fiber densities and mRNA encoding the activity dependent transcription factor npas4 in cerebral cortex of knockout mice. These novel data and previously reported human associations of CDH13 variants with addiction, individual differences in responses to stimulant administration and attention deficit hyperactivity disorder (ADHD) phenotypes suggest that levels of CDH13 expression, through mechanisms likely to include effects on mesocortical dopamine, influence stimulant reward and may contribute modestly to cognitive and locomotor phenotypes relevant to ADHD.
... In a GWAS conducted by Lasky-Su et al. (2008), the CDH13 rs655113 polymorphism was associated with the number of symptoms in ADHD. In a study by Arias-Vásquez et al. (2011) evaluating executive functions according to verbal working memory, visual spatial working memory, and inhibition tasks in children and adolescents with ADHD, the polymorphism of CDH13 rs11150556 was associated with verbal working memory performance in children with ADHD. Unlike previous studies, the insignificant results for the CDH13 rs6565113 and rs11150556 polymorphisms reported here could be related to the small size of our sample. ...
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Genetic factors play a major role in the etiopathogenesis of attention-deficit/hyperactivity disorder (ADHD). In this study, we aimed to investigate the relationship between the CDH13 (rs6565113, rs11150556) and LPHN3 (rs6551665, rs6858066, rs1947274, rs2345039) gene polymorphisms and ADHD. We also sought to examine possible relationships between these polymorphisms and the clinical course and treatment response in ADHD. A total of 120 patients (79% boys), aged 6 to 18 years, newly diagnosed (medication-naïve) with ADHD according to the DSM-5 and a group of 126 controls (74% girls) were enrolled in the study. We examined the association between the aforementioned polymorphisms and ADHD. Univariate and multivariate logistic regression analysis were used to evaluate factors influencing the treatment response of ADHD. A significant difference was found between ADHD and control groups in terms of genotype distribution of the LPHN3 rs6551665 and rs1947274 polymorphisms. The results also showed that having the GG genotype of rs6551665 and CC genotype of rs1947274 of the LPHN3 gene was associated with risk for ADHD, and this relationship was more prominent in male participants. In the multivariate logistic regression model established with variables shown to have a significant relationship with treatment response, the presence of the GG genotype of the LPHN3 rs6551665 polymorphism and high severity of ADHD assessed by CGI-S were associated with poor response to treatment. This study is the first study to investigate the relationship between ADHD and these polymorphisms among Turkish adolescents. Our results imply that the LPHN3 rs6551665 and rs1947274 polymorphisms have a significant effect on ADHD in a Turkish population, and support previous observations that the presence of the GG genotype of the LPHN3 rs6551665 polymorphism may be associated with poor response to treatment in ADHD.
... Interestingly, Cadherin 13 expression is found in neural substrates which are also associated with ADHD (e.g. frontal areas, striatum, substantia nigra, ventral tegmental area and locus coeruleus; Rivero et al., 2013) and clinical studies have demonstrated that CDH13 gene polymorphisms are also strongly associated with ADHD (Franke et al., 2009) and working memory performance in ADHD patients (Arias-Vásquez et al., 2011). ...
Article
Attention deficit/hyperactivity disorder (ADHD) is frequently associated with comorbid aggression and sleep disturbances. The sleep/wake cycle is under the control of the circadian system which is moderated by clock genes. Clock genes can regulate the transcription of monoamine oxidase A, which is involved in the degradation of monoamines. Disturbances in monoamine interaction with clock genes in those with monoamine gene polymorphisms may regulate susceptibility of ADHD and comorbid aggression/sleep disturbances. While monoamines influence circadian rhythm and clock gene expression, circadian rhythm components modulate aggressive behavior, and altered clock genes expression have been associated with ADHD. We propose a mechanism by which circadian rhythm and clock gene expression may influence ADHD and comorbid aggression through the modulation of neurotransmitters. The role of clock genes in ADHD patients with comorbid aggression awaits further research; therefore we also indicate directions for future studies to help increase understanding of the underlying mechanisms in ADHD with comorbid aggression and sleep disturbances.
... In addition, the deletion of cadherin-12 and cadherin-18 genes was correlated with SCZ [56]. These observations of defects in cadherin genes in patients with autism have also been observed in population studies in which the presence of these SNPs is correlated with individuals with problems in oral communication but not spatial memory [60,61]. These findings suggest that cadherins may be involved in the regulation of specific circuits related to verbal working memory. ...
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Synapses are complex structures that allow communication between neurons in the central nervous system. Studies conducted in vertebrate and invertebrate models have contributed to the knowledge of the function of synaptic proteins. The functional synapse requires numerous protein complexes with specialized functions that are regulated in space and time to allow synaptic plasticity. However, their interplay during neuronal development, learning, and memory is poorly understood. Accumulating evidence links synapse proteins to neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. In this review, we describe the way in which several proteins that participate in cell adhesion, scaffolding, exocytosis, and neurotransmitter reception from presynaptic and postsynaptic compartments, mainly from excitatory synapses, have been associated with several synaptopathies, and we relate their functions to the disease phenotype.
... Finally, the CDH13 gene has an important role in the regulation of neural cell growth. A linear regression analysis in a previous study indicated that an SNP in CDH13 has a strong association with verbal working memory performance, which has a proven correlation with ADHD (Arias-Vasquez et al., 2011). In addition, deletions in CDH13 were associated with autism, suggesting a role of CHD13 in the development of psychological disorders (Sanders et al., 2015). ...
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Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders. Several studies have confirmed the co-existence of other neuropsychiatric disorders with ADHD. Out of 106 individuals suspected to have ADHD, eight Saudi Arabian pediatric patients were diagnosed with ADHD using a dual assessment procedure based on highly significant scores from the international criteria for diagnosis; (full form DMS) DSM-5. Then, these patients were examined for the co-existence of autism and ADHD using different international diagnostic protocols. Four patients with combined ADHD and autism and four ADHD patients without autism were examined for the presence of genetic variants. Six variants (chr1:98165091, chr6:32029183, chr6:32035603, chr6:32064098, chr8:2909992, chr16:84213434) were identified in 75% of the patients with ADHD and autism, indicating that these genes may have a possible role in causing autism. Five variants (The chr2:116525960, chr15:68624396, chr15:91452595, chr15:92647645, and chr16:82673047) may increase to the severity of ADHD. This study recommends screening these eleven variants in ADHD cases and their relevant controls to confirm the prevalence in the Saudi population. It is recommended that future studies examine the 11 variants in detail.
... Strong candidate genes in this regard are those that escape X inactivation both in humans and mice: STS, MID1, KDM6A, EIF2S3, DDX3X, KDM5C, CA5B and CXorf38 (Yang et al., 2010). It is important to note, however, that specification of XCIe genes in both humans and mice is challenged by the recent observations that in mice alone XCIe genes can vary by organ (Arias-Vasquez et al., 2011; Lopes et al., 2010) and brain region (Gregg et al., 2010b). ...
... Several studies have linked disruptions in CDH13 function with susceptibility to ADHD. In particular, a single nucleotide polymorphism in CDH13 has been linked with altered performance in certain memory tests in ADHD sufferers (Arias-Vasquez et al. 2011;Rivero et al. 2013). Recent studies have shown that RNAi suppression Fig. 8 Increased apoptosis in GN11 cells and interneurons. ...
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Cortical interneurons are generated in the ganglionic eminences and migrate through the ventral and dorsal telencephalon before finding their final positions within the cortical plate. During early stages of migration, these cells are present in two well-defined streams within the developing cortex. In an attempt to identify candidate genes which may play a role in interneuron stream specification, we previously carried out a microarray analysis which identified a number of cadherin receptors that were differentially expressed in these streams, including Cadherin-13 (Cdh13). Expression analysis confirmed Cdh13 to be present in the preplate layer at E13.5 and, later in development, in some cortical interneurons and pyramidal cells. Analysis of Cdh13 knockout mice at E18.5, but not at E15.5, showed a reduction in the number of interneurons and late born pyramidal neurons and a concomitant increase in apoptotic cells in the cortex. These observations were confirmed in dissociated cell cultures using overexpression and short interfering RNAs (siRNAs) constructs and dominant negative inhibitory proteins. Our findings identified a novel protective role for Cdh13 in cortical neuron development.
... Interestingly, in silico functional annotations showed that the latter is predicted to be functional. Moreover, 16958387 was also reported to show a strong trend toward association (p = 0.00062) with the ADHD-verbal working memory task (Arias-Vásquez et al., 2011). The variant rs16958387 is mapped to an evolutionary conserved region at the TF binding sites of the Early B-Cell Factor 1 (EBF1) and P300 proteins. ...
Article
Converging evidence from candidate gene, genome-wide linkage, and association studies support a role of cadherins in the pathophysiology of five major psychiatric disorders including attention deficit hyperactivity disorder, autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). These molecules are transmembrane proteins which act as cell adhesives by forming adherens junctions (AJs) to bind cells within tissues. Members of the cadherin superfamily are also involved in biological processes such as signal transduction and plasticity that have been implicated in the etiology of major psychiatric conditions. Although there are over 110 genes mapped to the cadherin superfamily, our literature survey showed that evidence of association with psychiatric disorders is strongest for CDH7, CHD11, and CDH13. Gene enrichment analysis showed that those cadherin genes implicated in psychiatric disorders were overrepresented in biological processes such as in cell-cell adhesion (GO:0007156 & GO:0098742) and adherens junction organization (GO:0034332). Further, cadherin genes were also mapped to processes that have been linked to the development of psychiatric disorders such as nervous system development (GO:0007399). To further understand the role of cadherin SNPs implicated in psychiatric disorders, we utilized an in silico computational pipeline to functionally annotate associated variants. This analysis yielded eight variants mapped to PCDH1-13, CDH7, CDH11, and CDH13 that are predicted to be biologically functional. Functional genomic evaluation is now required to understand the molecular mechanism by which these variants might confer susceptibility to psychiatric disorders.
... Several studies have observed a reproducible association with attentiondeficit/hyperactivity disorder (ADHD) Lesch et al., 2008;Neale et al., 2008Neale et al., , 2010Zhou et al., 2008;Lionel et al., 2011) and comorbid conditions, specifically substance use and dependence (Uhl et al., 2008a,b;Treutlein et al., 2009). Furthermore, common CDH13 variants have been associated with cognitive functioning (e.g., performance in working memory tasks) in ADHD patients (Arias-Vasquez et al., 2011). Other studies relate CDH13 to depression (Sibille et al., 2009;Terracciano et al., 2010), bipolar disorder (Xu et al., 2014) and schizophrenia (Borglum et al., 2014). ...
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Background: During early prenatal stages of brain development, serotonin (5-HT)-specific neurons migrate through somal translocation to form the raphe nuclei and subsequently begin to project to their target regions. The rostral cluster of cells, comprising the median and dorsal raphe (DR), innervates anterior regions of the brain, including the prefrontal cortex. Differential analysis of the mouse 5-HT system transcriptome identified enrichment of cell adhesion molecules in 5-HT neurons of the DR. One of these molecules, cadherin-13 (Cdh13) has been shown to play a role in cell migration, axon pathfinding, and synaptogenesis. This study aimed to investigate the contribution of Cdh13 to the development of the murine brain 5-HT system. Methods: For detection of Cdh13 and components of the 5-HT system at different embryonic developmental stages of the mouse brain, we employed immunofluorescence protocols and imaging techniques, including epifluorescence, confocal and structured illumination microscopy. The consequence of CDH13 loss-of-function mutations on brain 5-HT system development was explored in a mouse model of Cdh13 deficiency. Results: Our data show that in murine embryonic brain Cdh13 is strongly expressed on 5-HT specific neurons of the DR and in radial glial cells (RGCs), which are critically involved in regulation of neuronal migration. We observed that 5-HT neurons are intertwined with these RGCs, suggesting that these neurons undergo RGC-guided migration. Cdh13 is present at points of intersection between these two cell types. Compared to wildtype controls, Cdh13-deficient mice display increased cell densities in the DR at embryonic stages E13.5, E17.5, and adulthood, and higher serotonergic innervation of the prefrontal cortex at E17.5. Conclusion: Our findings provide evidence for a role of CDH13 in the development of the serotonergic system in early embryonic stages. Specifically, we indicate that Cdh13 deficiency affects the cell density of the developing DR and the posterior innervation of the prefrontal cortex (PFC), and therefore might be involved in the migration, axonal outgrowth and terminal target finding of DR 5-HT neurons. Dysregulation of CDH13 expression may thus contribute to alterations in this system of neurotransmission, impacting cognitive function, which is frequently impaired in neurodevelopmental disorders including attention-deficit/hyperactivity and autism spectrum disorders.
... Arias-Vázquez et al. studied a possible association between CDH13 and neurocognitive endophenotypes. One SNP showed to be associated with performance on a verbal working memory test [50]. ...
Article
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder affecting 5.29% of children worldwide. It presents a heterogeneous clinical expression, and both environmental and genetic factors are involved in the etiology. Despite high heritability estimates, identification of genes that confer susceptibility to ADHD has been a slow and difficult process. The first genetic studies targeted dopaminergic genes, but the effects were small and only explained a small portion of ADHD heritability. Recent studies focus on the identification of novel genes and pathways that may underlie ADHD. The main goal of this review is to present evidence from genome-wide association, copy number variation and family-based studies of genetic susceptibility to ADHD. The challenges involved to disclose ADHD susceptibility genes will be reviewed in order to provide directions for future studies.
... In the cluster of genes that were largely differentially expressed (FDR < 0.05, Student's t-test) we found prominent cancer-related genes such as EGF. Furthermore, we found CDH13, a calcium-dependent cell-cell adhesion gene that is associated with working memory performance in attention deficit disorders and a regulator of neural cell growth [34]. Also, we observed a member of the MAP kinase family, MAPK10, that plays regulatory roles in signaling pathways during neuronal apoptosis through its phosphorylation and nuclear localization [35]. ...
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Background: eQTL analysis is a powerful method that allows the identification of causal genomic alterations, providing an explanation of expression changes of single genes. However, genes mediate their biological roles in groups rather than in isolation, prompting us to extend the concept of eQTLs to whole gene pathways. Methods: We combined matched genomic alteration and gene expression data of glioblastoma patients and determined associations between the expression of signaling pathways and genomic copy number alterations with a non-linear machine learning approach. Results: Expectedly, over-expressed pathways were largely associated to tag-loci on chromosomes with signature alterations. Surprisingly, tag-loci that were associated to under-expressed pathways were largely placed on other chromosomes, an observation that held for composite effects between chromosomes as well. Indicating their biological relevance, identified genomic regions were highly enriched with genes having a reported driving role in gliomas. Furthermore, we found pathways that were significantly enriched with such driver genes. Conclusions: Driver genes and their associated pathways may represent a functional core that drive the tumor emergence and govern the signaling apparatus in GBMs. In addition, such associations may be indicative of drug combinations for the treatment of brain tumors that follow similar patterns of common and diverging alterations.
... In a review of five genome-wide association studies, Franke et al. (2009) noted that, whereas few of the 'classic' candidate genes, such as DAT4 a dopamine transporter gene, showed a reliable association with ADHD, the cell adhesion molecule cadherin CDH13 was the most common associate among the studies (also see Banaschewski et al., 2010). CDH13 is associated with many of the symptoms of ADHD (Mick et al., 2011), and with impaired working memory (Arias-Vásquez et al., 2011). CDH13 plays many roles in the brain (Rivero et al., 2012), among them a negative growth regulator for astrocytes (Huang et al., 2003). ...
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KILLEEN, P.R., V.A. Russell and J.A. Sergeant. A behavioral neuroenergetics theory of ADHD. NEUROSCI BIOBEHAV REV 37(4) XXX_XXX 2013- Energetic insufficiency in neurons due to inadequate lactate supply is implicated in several neuropathologies, including attention-deficit/hyperactivity disorder (ADHD). By formalizing the mechanism and implications of such constraints on function, the behavioral Neuroenergetics Theory (NeT) predicts the results of many neuropsychological tasks involving individuals with ADHD and kindred dysfunctions, and entails many novel predictions. The associated diffusion model predicts that response times will follow a mixture of Wald distributions from the attentive state, and ex-Wald distributions after attentional lapses. It is inferred from the model that ADHD participants can bring only 75-85% of the neurocognitive energy to bear on tasks, and allocate only about 85% of the cognitive resources of comparison groups. Parameters derived from the model in specific tasks predict performance in other tasks, and in clinical conditions often associated with ADHD. The primary action of therapeutic stimulants is the increase they cause in norepinephrine, which activates glial adrenoceptors, increasing the release of lactate from astrocytes to fuel depleted neurons. The theory is aligned with other approaches and integrated with more general theories of ADHD. Therapeutic implications are explored.
... Furthermore, rs6565113, one of its intronic SNPs (Arias-Vásquez et al., 2011), was associated with ADHD in four of the so far conducted GWAS (Lasky-Su et al., 2008;Lesch et al., 2008;Neale et al., 2010a;Zhou et al., 2008) and in one meta-analysis (Neale et al., 2010b;cf. 1.1.2.3). ...
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Background: Attention-deficit/ hyperactivity disorder (ADHD) ranges among the most common neurodevelopmental disorders worldwide with a prevalence of 3-12% in childhood and 1-5% for adults. Over the last decade extensive genetic research has been conducted in order to determine its causative genetic factors. None of the so far identified susceptibility genes, however, could explain the estimated ADHD heritability of 76%. In this thesis one of the most promising candidates -Cadherin 13 (Cdh13) - was examined in terms of its influence on the central serotonergic (5-HT) system. In addition to that, the Cdh13 protein distribution pattern was analysed over time. Methods: The developing serotonergic system was compared over three embryonic and postnatal stages (E13.5, E17.5 and P7) in different Cdh13 genotypes (WT, HZ and KO) using immunohistochemistry and various double staining protocols. Results: The raphe nuclei of the 5-HT system develop in spite of Cdh13 absence and show a comparable mature constellation. The cells in the KO, however, are slightly more scattered than in the WT. Furthermore the dynamics of their formation is altered, with a transient delay in migration at E13.5. In early developmental stages the total amount of serotonergic cells is reduced in KO and HZ, though their proportional distribution to the raphe nuclei stays constant. Strikingly, at P7 the absolute numbers are comparable again. Concerning the Cdh13 protein, it shows high concentrations on fibres running through hindbrain and midbrain areas at E13.5. This, however, changes over time, and it becomes more evenly spread until P7. Furthermore, its presence in serotonergic cells could be visualised using confocal microscopy. Since the described pattern is only in parts congruent to the localisation of serotonergic neurons, it is most likely that Cdh13 is present in other developing neurotransmitter systems, such as the dopaminergic one, as well. Conclusion: It could be proven that Cdh13 is expressed in serotonergic cells and that its knockout does affect the developing serotonergic system to some degree. Its absence, however, only slightly and transiently affects the measured parameters of serotonergic system development, indicating a possible compensation of CDH13 function by other molecules in the case of Cdh13 deficiency. In addition further indicators could be found for an influence of Cdh13 on outgrowth and path finding of neuronal processes.
... It is also expressed during embryogenesis and neuronal development, where it is associated with migration of serotonergic neurons in the dorsal raphe nucleus, establishing projections to the lateral and medial thalamus, hypothalamus and cerebellum (Rivero et al., 2013;Forero et al., 2017). In addition, several studies revealed CDH13 variants associated with memory impairment (Salatino-Oliveira et al., 2011), deficits in verbal working memory (Arias-Vasquez et al., 2011), IQ discrepancy in autism (Chapman et al., 2011), as well as hyperactivity/impulsivity, specifically during childhood and in adolescents (Salatino-Oliveira et al., 2015). However, little is known if the genetic association is rooted in a loss-or gain-of-function of CDH13 in those patients. ...
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Objective: Cadherin-13 (CDH13), a member of the calcium-dependent cell adhesion molecule family, has been linked to neurodevelopmental disorders, including autism spectrum (ASD) and attention-deficit/hyperactivity (ADHD) disorders, but also to depression. In the adult brain, CDH13 expression is restricted e.g. to the presynaptic compartment of inhibitory GABAergic synapses in the hippocampus and Cdh13 knockout mice show an increased inhibitory drive onto hippocampal CA1 pyramidal neurons, leading to a shift in excitatory/inhibitory balance. CDH13 is also moderating migration of serotonergic neurons in the dorsal raphe nucleus, establishing projections preferentially to the thalamus and cerebellum during brain development. Furthermore, CDH13 is upregulated by chronic stress as well as in depression, suggesting a role in early-life adaptation to stressful experience. Here, we therefore investigated the interaction between Cdh13 variation and neonatal maternal separation (MS) in mice. Methods: Male and female wild-type (Cdh13+/+), heterozygous (Cdh13+/-) and homozygous (Cdh13-/-) knockout mice exposed to MS, or daily handling as control, were subjected to a battery of behavioural tests to assess motor activity, learning and memory as well as anxiety-like behaviour. A transcriptome analysis of the hippocampus was performed in an independent cohort of mice which was exposed to MS or handling, but remained naïve for behavioural testing. Results: MS lead to increased anxiety-like behaviour in Cdh13-/- mice compared to the other two MS groups. Cdh13-/- mice showed a context-dependent effect on stress- and anxiety-related behaviour, impaired extinction learning following contextual fear conditioning and decreased impulsivity, as well as a mild decrease in errors in the Barnes maze and reduced risk-taking in the light-dark transition test after MS. We also show sex differences, with increased locomotor activity in female Cdh13-/- mice, but unaltered impulsivity and activity in male Cdh13-/- mice. Transcriptome analysis revealed several pathways associated with cell surface/adhesion molecules to be altered following Cdh13 deficiency, together with an influence on endoplasmic reticulum function. Conclusion: MS resulted in increased stress resilience, increased exploration and an overall anxiolytic behavioural phenotype in male Cdh13+/+ and Cdh13+/- mice. Cdh13 deficiency, however, obliterated most of the effects caused by early-life stress, with Cdh13-/- mice exhibiting delayed habituation, no reduction of anxiety-like behaviour and decreased fear extinction. Our behavioural findings indicate a role of CDH13 in the programming of and adaptation to early-life stress. Finally, our transcriptomic data support the view of CDH13 as a neuroprotective factor as well as a mediator in cell-cell interactions, with an impact on synaptic plasticity.
... [20][21][22][23] Özellikle çalışma belleği ile ilgili sorunlar, aşırı hareketlilik ve dürtüsellik belirtilerinden sorumlu olduğu düşünülmektedir. 21,24,25 2015 yılında yapılan bir çalışmada ise CDH13-hareketlilik/dürtüsellik belirtileri genç DEHB'li bireylerde ilişkili bulunmuş iken, erişkinlerde ilişkili bulunmamıştır. 25 GRIN2A geni iyonotropik glutamat reseptörlerinden N-metil-D-aspartat 2A reseptörünün sentezinden sorumlu gendir. ...
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Dikkat eksikliği hiperaktivite bozukluğu (DEHB); dikkatsizlik, aşırı hareketlilik ve dürtüsellik belirtileriyle seyreden nörogelişimsel bir bozukluktur. DEHB’nin etiyolojisinde genetik, sosyal ve fiziksel faktörlerin etkili olduğu düşünülmektedir. Bu çalışmada, DEHB’nin genetik yönünü araştıran çalışmaların gözden geçirilmesi hedeflenmiştir. Bu amaçla Pubmed, Google Akademik ve diğer çevrimiçi arama motorları taranmış, elde edilen veriler temel bilgilerle birleştirilerek sunulmaya çalışılmıştır. DEHB etiyolojisinde genetik etkenlerle ilgili çalışmalar, bu araştırmada “Genetik bağıntı analizi çalışmaları (Genetic linkage studies)”, “Aday gen ilişkili çalışmalar (Candidate-gene association studies)”, “Geniş çaplı genom çalışmaları (Genome-wide association studies)”, “Gen kopya sayısı varyantları ile ilişkili çalışmalar (Copy number variation studies)” başlıkları altında incelenmiştir. DEHB’den sorumlu olduğu öne sürülen genetik faktörlerle ilgili çalışmaların sonuçlarının çelişkili olması, bozukluğun heterojenliğine, genetik ve çevresel etkenlerin oluşturduğu epigenetik değişikliklerin etkisine ve çalışmalardaki istatistiksel kısıtlılığa bağlı görünmektedir. Bu sınırlamaların aşılabilmesi için, daha büyük örneklemlerde genetik ve çevresel faktörlerin aynı anda ele alındığı çalışmalara gereksinim duyulmaktadır. Anah tar Ke li me ler: Dikkat eksikliği hiperaktivite bozukluğu; DEHB; genetik; etiyoloji
... Some of these polymorphisms and/or genes have not been confirmed to be significantly associated by meta-analysis. However, those that have been confirmed include a 148bp dinucleotide repeat allele 18.5 kb from the DRD5 gene (Kustanovich et al., 2004); four TACR1 SNPs previously associated with bipolar disorder and alcoholism (Yan, Hunt, & Stanford, 2009); the 861G allele of the HTR1B gene (Hawi et al., 2002;Quist et al., 2003); SNP in DBH (rs2519152) (Daly, Hawi, Fitzgerald, & Gill, 1999); two functional mutations, rs1108580 and rs1611115, associated with plasma levels of DBH (Gizer et al., 2009); allelic association between the ADRA1A gene and ADHD (Elia et al., 2009); a silent polymorphism in intron 7 (rs1800532) of the TPH1 gene (Li et al., 2006); the long promoter variant of the SLC5A4 gene associated with more rapid reuptake of serotonin than the short allele (Lesch et al., 1996); SNPs in SNAP25 gene (rs3746544) (Gizer et al., 2009); intronic SNP rs11150556 in CDH13 gene associated with performance on the verbal working memory task in ADHD (Arias-Vásquez et al., 2011). A detailed review on this issue can be found in Sharp et al. (2009). ...
Article
A number of polymorphisms have been implicated in different neuropsychiatric and neurological disorders. Polymorphisms in neurological disorders with a central immune component are well described, mainly due to their role in increasing neurodegeneration. For example, the role of polymorphisms in Alzheimer's disease in accumulation of amyloid plaques is now well established. In contrast, polymorphisms resulting in or affecting psychiatric disorders are less well studied and frequently are not replicated by meta-analysis. Furthermore, even if a significant association has been confirmed, the role of the identified polymorphism in causing and/or augmenting the disorder is often difficult to rationalize. Here, we review polymorphisms found associated with different neuroinflammatory and neuropsychiatric disorders and discuss the role of next generation sequencing in early diagnosis and treatment and as a tool in studying their functional consequences.
... Finally, a meta-analysis of linkage scans for ADHD identified a genomic region containing CDH13 (16q21-16q24) [66]. Based on these results, a candidate gene study of CDH13 and ADHD was performed that found a gene-wide significant association at one SNP (rs11150556) [67]. In addition, CDH13 has also been implicated by GWAS in depression (rs10514585) [68], extraversion (rs4783307, rs8056579) [69], agreeableness (rs9940706) [69] and response to antipsychotic therapy (rs17216786) [70], as well as in a meta-analysis for extraversion (rs8057458) [71]. ...
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Both the subjective response to d-amphetamine and the risk for amphetamine addiction are known to be heritable traits. Because subjective responses to drugs may predict drug addiction, identifying alleles that influence acute response may also provide insight into the genetic risk factors for drug abuse. We performed a Genome Wide Association Study (GWAS) for the subjective responses to amphetamine in 381 non-drug abusing healthy volunteers. Responses to amphetamine were measured using a double-blind, placebo-controlled, within-subjects design. We used sparse factor analysis to reduce the dimensionality of the data to ten factors. We identified several putative associations; the strongest was between a positive subjective drug-response factor and a SNP (rs3784943) in the 8(th) intron of cadherin 13 (CDH13; P = 4.58×10(-8)), a gene previously associated with a number of psychiatric traits including methamphetamine dependence. Additionally, we observed a putative association between a factor representing the degree of positive affect at baseline and a SNP (rs472402) in the 1(st) intron of steroid-5-alpha-reductase-α-polypeptide-1 (SRD5A1; P = 2.53×10(-7)), a gene whose protein product catalyzes the rate-limiting step in synthesis of the neurosteroid allopregnanolone. This SNP belongs to an LD-block that has been previously associated with the expression of SRD5A1 and differences in SRD5A1 enzymatic activity. The purpose of this study was to begin to explore the genetic basis of subjective responses to stimulant drugs using a GWAS approach in a modestly sized sample. Our approach provides a case study for analysis of high-dimensional intermediate pharmacogenomic phenotypes, which may be more tractable than clinical diagnoses.
... May act as a negative regulator of neurite outgrowth and axon guidance required for development and synaptic plasticity (Rivero et al., 2013). Contributes to deficits in impulse control, as shown by polymorphisms linking violent behaviour (Takeuchi et al., 2000), hyperactivity/ impulsivity and impaired working memory in ADHD (Salatino-Oliveira et al., 2015; Arias-Vasquez et al., 2011), as well as alcohol (Treutlein et al., 2009) and (met)amphetamine (Hart et al., 2012;Uhl et al., 2008) ...
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... Analysis of additional, ADHD-related phenotypes in individuals which generated the results reported by Neale et al. (2008) also points to CDH13 (Figure 1). In these studies, CDH13 was found to be associated with a quantitative phenotype of ADHD symptoms (Lasky-Su et al., 2008a), the age at onset of ADHD symptoms (Lasky-Su et al., 2008b) and neurocognitive executive functioning: response inhibition, verbal and visuo-spatial working memory (Arias-V asquez et al., 2011). ...
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Neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are disorders of mostly unknown etiopathogenesis, for which both genetic and environmental influences are expected to contribute to the phenotype observed in patients. Changes at all levels of brain function, from network connectivity between brain areas, over neuronal survival, synaptic connectivity and axonal growth, down to molecular changes and epigenetic modifications are suspected to play a key roles in these diseases, resulting in life-long behavioural changes. Genome-wide association as well as copy-number variation studies have linked cadherin-13 (CDH13) as a novel genetic risk factor to neuropsychiatric and neurodevelopmental disorders. CDH13 is highly expressed during embryonic brain development, as well as in the adult brain, where it is present in regions including the hippocampus, striatum and thalamus (among others) and is upregulated in response to chronic stress exposure. It is however unclear how CDH13 interacts with environmentally relevant cues, including stressful triggers, in the formation of long-lasting behavioural and molecular changes. It is currently unknown how the environment influences CDH13 and which long term changes in behaviour and gene expression are caused by their interaction. This work therefore investigates the interaction between CDH13 deficiency and neonatal maternal separation (MS) in mice with the aim to elucidate the function of CDH13 and its role in the response to early-life stress (ELS). For this purpose, mixed litters of wild-type (Cdh13+/+), heterozygous (Cdh13+/-) and homozygous knockout (Cdh13-/-) mice were maternally separated from postnatal day 1 (PN1) to postnatal day 14 (PN14) for 3 hours each day (180MS; PN1-PN14). In a first series of experiments, these mice were subjected to a battery of behavioural tests starting at 8 weeks of age in order to assess motor activity, memory functions as well as measures of anxiety. Subsequently, expression of RNA in various brain regions was measured using quantitativ real-time polymerase chain reaction (qRT-PCR). A second cohort of mice was exposed to the same MS procedure, but was not behaviourally tested, to assess molecular changes in hippocampus using RNA sequencing. Behavioural analysis revealed that MS had an overall anxiolytic-like effect, with mice after MS spending more time in the open arms of the elevated-plus-maze (EPM) and the light compartment in the light-dark box (LDB). As a notable exception, Cdh13-/- mice did not show an increase of time spent in the light compartment after MS compared to Cdh13+/+ and Cdh13+/- MS mice. During the Barnes-maze learning task, mice of most groups showed a similar ability in learning the location of the escape hole, both in terms of primary latency and primary errors. Cdh13-/- control (CTRL) mice however committed more primary errors than Cdh13-/- MS mice. In the contextual fear conditioning (cFC) test, Cdh13-/- mice showed more freezing responses during the extinction recall, indicating a reduced extinction of fear memory. In the step-down test, an impulsivity task, Cdh13-/- mice had a tendency to wait longer before stepping down from the platform, indicative of more hesitant behaviour. In the same animals, qRT-PCR of several brain areas revealed changes in the GABAergic and glutamatergic systems, while also highlighting changes in the gatekeeper enzyme Glykogensynthase-Kinase 3 (Gsk3a), both in relation to Cdh13 deficiency and MS. Results from the RNA sequencing study and subsequent gene-set enrichment analysis revealed changes in adhesion and developmental genes due to Cdh13 deficiency, while also highlighting a strong link between CDH13 and endoplasmatic reticulum function. In addition, some results suggest that MS increased pro-survival pathways, while a gene x environment analysis showed alterations in apoptotic pathways and migration, as well as immune factors and membrane metabolism. An analysis of the overlap between gene and environment, as well as their interaction, highlighted an effect on cell adhesion factors, underscoring their importance for adaptation to the environment. Overall, the stress model resulted in increased stress resilience in Cdh13+/+ and Cdh13+/- mice, a change absent in Cdh13-/- mice, suggesting a role of CDH13 during programming and adaptation to early-life experiences, that can results in long-lasting consequences on brain functions and associated behaviours. These changes were also visible in the RNA sequencing, where key pathways for cell-cell adhesion, neuronal survival and cell-stress adaptation were altered. In conclusion, these findings further highlight the role of CDH13 during brain development, while also shedding light on its function in the adaptation and response during (early life) environmental challenges.
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Genetic contribution to the development of attention deficit hyperactivity disorder (ADHD) is well established. Seven independent genome-wide linkage scans have been performed to map loci that increase the risk for ADHD. Although significant linkage signals were identified in some of the studies, there has been limited replications between the various independent datasets. The current study gathered the results from all seven of the ADHD linkage scans and performed a Genome Scan Meta Analysis (GSMA) to identify the genomic region with most consistent linkage evidence across the studies. Genome-wide significant linkage (P(SR) = 0.00034, P(OR) = 0.04) was identified on chromosome 16 between 64 and 83 Mb. In addition there are nine other genomic regions from the GSMA showing nominal or suggestive evidence of linkage. All these linkage results may be informative and focus the search for novel ADHD susceptibility genes.
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Results of behavioral genetic and molecular genetic studies have converged to suggest that genes substantially contribute to the development of attention deficit/hyperactivity disorder (ADHD), a common disorder with an onset in childhood. Yet, despite numerous linkage and candidate gene studies, strongly consistent and replicable association has eluded detection. To search for ADHD susceptibility genes, we genotyped approximately 600,000 SNPs in 958 ADHD affected family trios. After cleaning the data, we analyzed 438,784 SNPs in 2,803 individuals comprising 909 complete trios using ADHD diagnosis as phenotype. We present the initial TDT findings as well as considerations for cleaning family-based TDT data. None of the SNP association tests achieved genome-wide significance, indicating that larger samples may be required to identify risk loci for ADHD. We additionally identify a systemic bias in family-based association, and suggest that variable missing genotype rates may be the source of this bias.
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Attention deficit hyperactivity disorder (ADHD) is a complex condition with environmental and genetic etiologies. Up to this point, research has identified genetic associations with candidate genes from known biological pathways. In order to identify novel ADHD susceptibility genes, 600,000 SNPs were genotyped in 958 ADHD proband-parent trios. After applying data cleaning procedures we examined 429,981 autosomal SNPs in 909 family trios. We generated six quantitative phenotypes from 18 ADHD symptoms to be used in genome-wide association analyses. With the PBAT screening algorithm, we identified 2 SNPs, rs6565113 and rs552655 that met the criteria for significance within a specified phenotype. These SNPs are located in intronic regions of genes CDH13 and GFOD1, respectively. CDH13 has been implicated previously in substance use disorders. We also evaluated the association of SNPs from a list of 37 ADHD candidate genes that was specified a priori. These findings, along with association P-values with a magnitude less than 10(-5), are discussed in this manuscript. Seventeen of these candidate genes had association P-values lower then 0.01: SLC6A1, SLC9A9, HES1, ADRB2, HTR1E, DDC, ADRA1A, DBH, DRD2, BDNF, TPH2, HTR2A, SLC6A2, PER1, CHRNA4, SNAP25, and COMT. Among the candidate genes, SLC9A9 had the strongest overall associations with 58 association test P-values lower than 0.01 and multiple association P-values at a magnitude of 10(-5) in this gene. In sum, these findings identify novel genetic associations at viable ADHD candidate genes and provide confirmatory evidence for associations at previous candidate genes. Replication of these results is necessary in order to confirm the proposed genetic variants for ADHD.
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The distinction between hyperactivity and conduct disorder was explored in a mixed group of 64 children referred to psychiatric clinics because of antisocial or disruptive behaviour. A semi-structured interview measure (the Parental Account of Children's Symptoms, PACS) proved to have adequate inter-rater reliability, internal consistency and factorial validity. The PACS scales of defiance and hyperactivity, and similar subscales from Conners' Teacher Rating Scale, were tested against laboratory and clinical measures of activity, attention, cognitive performance, psychosocial background and family relationships. The hyperactivity (but not the defiance) scales were associated with greater activity, younger age, poorer cognitive performance and abnormalities on a developmental neurological examination. The defiance (but not the hyperactivity) scales were associated with impairment of family relationships and adverse social factors. It was concluded that a dimension of inattentive, restless activity should be separated from one of antisocial, defiant conduct in children with psychiatric disorder.
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This article reports four experiments on the ability to inhibit responses in simple and choice reaction time (RT) tasks. Subjects responding to visually presented letters were occasionally presented with a stop signal (a tone) that told them not to respond on that trial. The major dependent variables were (a) the probability of inhibiting a response when the signal occurred, (b) mean and standard deviation (SD) of RT on no-signal trials, (c) mean RT on trials on which the signal occurred but subjects failed to inhibit, and (d) estimated RT to the stop signal. A model was proposed to estimated RT to the stop signal and to account for the relations among the variables. Its main assumption is that the RT process and the stopping process race, and response inhibition depends on which process finishes first. The model allows us to account for differences in response inhibition between tasks in terms of transformations of stop-signal delay that represent the re