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Functional properties of rare missense variants of human CDH13 found in adult attention deficit/hyperactivity disorder (ADHD) patients.

ABSTRACT: The CDH13 gene codes for T-cadherin, a GPI-anchored protein with cell adhesion properties that is highly expressed in the brain and cardiovascular system. Previous studies have suggested that CDH13 may be a promising candidate gene for Attention Deficit/Hyperactivity Disorder (ADHD). The aims of this study were to identify, functionally characterize, and estimate the frequency of coding CDH13 variants in adult ADHD patients and controls. We performed sequencing of the CDH13 gene in 169 Norwegian adult ADHD patients and 63 controls and genotyping of the identified variants in 641 patients and 668 controls. Native and green fluorescent protein tagged wild type and variant CDH13 proteins were expressed and studied in CHO and HEK293 cells, respectively. Sequencing identified seven rare missense CDH13 variants, one of which was novel. By genotyping, we found a cumulative frequency of these rare variants of 2.9% in controls and 3.2% in ADHD patients, implying that much larger samples are needed to obtain adequate power to study the genetic association between ADHD and rare CDH13 variants. Protein expression and localization studies in CHO cells and HEK293 cells showed that the wild type and mutant proteins were processed according to the canonical processing of GPI-anchored proteins. Although some of the mutations were predicted to severely affect protein secondary structure and stability, no significant differences were observed between the expression levels and distribution of the wild type and mutant proteins in either HEK293 or CHO cells. This is the first study where the frequency of coding CDH13 variants in patients and controls is reported and also where the functional properties of these variants are examined. Further investigations are needed to conclude whether CDH13 is involved in the pathogenesis of ADHD or other conditions.

SUBMITTER: Mavroconstanti T

PROVIDER: S-EPMC3731280 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Functional properties of rare missense variants of human CDH13 found in adult attention deficit/hyperactivity disorder (ADHD) patients.

Mavroconstanti Thegna T Johansson Stefan S Winge Ingeborg I Knappskog Per M PM Haavik Jan J

PloS one 20130801 8

The CDH13 gene codes for T-cadherin, a GPI-anchored protein with cell adhesion properties that is highly expressed in the brain and cardiovascular system. Previous studies have suggested that CDH13 may be a promising candidate gene for Attention Deficit/Hyperactivity Disorder (ADHD). The aims of this study were to identify, functionally characterize, and estimate the frequency of coding CDH13 variants in adult ADHD patients and controls. We performed sequencing of the CDH13 gene in 169 Norwegian ...[more]

PMID: 23936508

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Project description:While psychiatric comorbidities of attention-deficit/hyperactivity disorder (ADHD) have been extensively explored, less attention has been paid to somatic conditions possibly associated with this disorder. However, mounting evidence in the last decade pointed to a possible significant association between ADHD and certain somatic conditions, including obesity. This papers provides an update of a previous systematic review on the relationship between obesity and ADHD (Cortese and Vincenzi, Curr Top Behav Neurosci 9:199-218, 2012), focusing on pertinent peer-reviewed empirical papers published since 2012. We conducted a systematic search in PubMed, Ovid, and Web of Knowledge databases (search dates: from January 1st, 2012, to July 16th, 2016). We retained a total of 41 studies, providing information on the prevalence of obesity in individuals with ADHD, focusing on the rates of ADHD in individuals with obesity, or reporting data useful to gain insight into possible mechanisms underlying the putative association between ADHD and obesity. Overall, over the past 4 years, an increasing number of studies have assessed the prevalence of obesity in individuals with ADHD or the rates of ADHD in patients with obesity. Although findings are mixed across individual studies, meta-analytic evidence shows a significant association between ADHD and obesity, regardless of possible confounding factors such as psychiatric comorbidities. An increasing number of studies have also addressed possible mechanisms underlying the link between ADHD and obesity, highlighting the role, among others, of abnormal eating patterns, sedentary lifestyle, and possible common genetic alterations. Importantly, recent longitudinal studies support a causal role of ADHD in contributing to weight gain. The next generation of studies in the field should explore if and to which extent the treatment of comorbid ADHD in individuals with obesity may lead to long-term weight loss, ultimately improving their overall well-being and quality of life.

Project description:Attention-deficit/hyperactivity disorder (ADHD) is a common, early-onset and enduring developmental disorder whose underlying etiological and neurobiological processes are the current focus of major research. Research strategies have made considerable effort in elucidating the complex genetic architecture of ADHD and indicate various pathways from genotype to phenotype. Understanding ADHD as a neuropsychiatric disorder enabled to investigate markers of neural activity as endophenotypes to better explain the link from gene to symptomatology (the so-called imaging genetics approach). Overcoming the originally rather restrictive requirements for an endophenotype, imaging genetics studies are supposed to offer a much more flexible and hypothesis-driven approach towards the etiology of ADHD. Although 1) ADHD often persists into adulthood, thus remaining a prevalent disorder, and 2) imaging genetics provides a promising research approach, a review on imaging genetics in adult ADHD - as available for childhood ADHD (Durston 2010) - is lacking. In this review, therefore, findings from the few available imaging genetics studies in adult ADHD will be summarized and complemented by relevant findings from healthy controls and children with ADHD that are considered important for the adult ADHD imaging genetics approach. The studies will be reviewed regarding implications for basic research and possible practical applications. Imaging genetics studies in adult ADHD have the potential to further clarify pathophysiological pathways and mechanisms, to derive new testable hypotheses, to investigate genetic interaction effects and to partly influence practical applications. In combination with other research strategies, they can incrementally foster the understanding of relevant processes in a more comprehensive way. Current limitations comprise the incapability to discover new genes, a high genetic load in patients potentially obscuring the effect of single candidate genes, the mostly unknown heritability of the endophenotype and the heterogeneous manifestation of ADHD.

Project description:Background. The number of students with Attention Deficit/Hyperactivity Disorder (ADHD) enrolled in colleges and universities has increased markedly over the past few decades, giving rise to questions about how best to document symptoms and impairment in the post-secondary setting. The aim of the present study was to investigate the utility and psychometric properties of a widely-used rating scale for adults with ADHD, the Adult ADHD Self-Report Scale (ASRS-V1.1), in a sample of post-secondary students with ADHD. Methods. A total of 135 college students (mean age = 24, 42% males) with ADHD were recruited from Student Disability Services in post-secondary institutions. We compared informant responses on the ASRS administered via different modalities. First, students' self-report was ascertained using the ASRS Screener administered via telephone interview, in which they were asked to provide real-life examples of behavior for each of the six items. Next, students self-reported symptoms on the 18-item paper version of the ASRS Symptom Checklist administered about 1-2 weeks later, and a collateral report using an online version of the 18-item ASRS Symptom Checklist. Students also completed self-report measures of everyday cognitive failure (CFQ) and executive functioning (BDEFS). Results. Results revealed moderate to good congruency between the 18-item ASRS-Self and ASRS-Collateral reports (correlation = .47), and between student self-report on the 6-item telephone-based and paper versions of the ASRS, with the paper version administered two weeks later (correlation = .66). The full ASRS self-report was related to impairment, such as in executive functioning (correlation = .63) and everyday cognitive failure (correlation = .74). Executive functioning was the only significant predictor of ASRS total scores. Discussion. Current findings suggest that the ASRS provides an easy-to-use, reliable, and cost-effective approach for gathering information about current symptoms of ADHD in college and university students. Collateral reports were moderately related to self-reports, although we note the difficulty in obtaining informant reports for this population. Use of a telephone interview to elicit behavioral descriptions for each item may be useful in future research that is required to specifically test the utility of the ASRS in, for example, documenting and confirming current reports of impairment due to ADHD symptoms and its positive and negative predictive power for diagnosis.

Dataset Information

Functional properties of rare missense variants of human CDH13 found in adult attention deficit/hyperactivity disorder (ADHD) patients.

Publications

Functional properties of rare missense variants of human CDH13 found in adult attention deficit/hyperactivity disorder (ADHD) patients.

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