Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

Moya, Pablo R.; Dodman, Nicholas H.; Timpano, Kiara R.; Rubenstein, Liza M.; Rana, Zaker; Fried, Ruby L.; Reichardt, Louis F.; Heiman, Gary A.; Tischfield, Jay A.; King, Robert A.; Galdzicka, Marzena; Ginns, Edward I.; Wendland, Jens R.

doi:10.1038/ejhg.2012.245

Cited by 42 publications

(35 citation statements)

References 64 publications

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“…Micro-arrays have also been used for studying de novo copy number variations (CNVs) by using parent–child trios; identifying de novo mutations possibly underlying TS can be enhanced by investigating non-familial forms of TS through the analysis of apparently simplex trios (i.e., an affected individual with both parents unaffected) [ 15 , 21 , 25 , 26 ]. The studies of rare variants have yielded intriguing findings that implicate genes involved in histaminergic and serotonergic pathways ([ 27 – 29 ], see also [ 30 ]) and genes involved in promoting dendritic growth [ 20 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

The Tourette International Collaborative Genetics (TIC Genetics) study, finding the genes causing Tourette syndrome: objectives and methods

Dietrich

Fernandez

King

et al. 2014

Eur Child Adolesc Psychiatry

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Tourette syndrome (TS) is a neuropsychiatric disorder characterised by motor and phonic tics and often accompanied by obsessive-compulsive disorder and attention-deficit/hyperactivity disorder. While the evidence for a genetic contribution is strong, its exact nature has yet to be clarified fully. There is now mounting evidence that the genetic risks for TS include both common and rare variants and may involve complex multigenic inheritance or, in rare cases, a single major gene. Based on recent progress in many other common disorders with ostensibly similar genetic architectures, it is clear that large-scale patient cohorts and open-access repositories will be essential to further advance the field. To that end, the large multicenter Tourette International Collaborative Genetics (TIC Genetics) study was established. The goal of the TIC Genetics study is to undertake a comprehensive gene discovery effort, focusing both on familial genetic variants with large effects within multiply affected pedigrees and on de novo mutations ascertained through the analysis of apparently sporadic (non-familial) trios. The clinical data and biomaterials (DNA, transformed cell lines, RNA) are part of a sharing repository located within the National Institute for Mental Health Center for Collaborative Genetic Studies on Mental Disorders, USA, and will be made available to the broad scientific community. This resource will ultimately facilitate better understanding of the pathophysiology of TS and related disorders and the development of new therapies. Here, we describe the objectives and methods of the TIC Genetics study.

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Section: Introductionmentioning

confidence: 99%

The Tourette International Collaborative Genetics (TIC Genetics) study, finding the genes causing Tourette syndrome: objectives and methods

Dietrich

Fernandez

King

et al. 2014

Eur Child Adolesc Psychiatry

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“…An OCD has been characterized in the Doberman pinscher breed of dogs, and was shown to have a highly significant genetic association with alleles of the Cadherin 2 ( CDH2 ) gene region [2] , [3] . Rare missense variants in CDH2 are associated with OCD and Tourette disorder in humans [4] . These observations suggest that the CDH2 gene may contribute to OCD; therefore, we speculated that variants in the CDH2 gene might be involved in the circling behavior seen in the BM.…”

Section: Introductionmentioning

confidence: 99%

Balancing Selection on CDH2 May Be Related to the Behavioral Features of the Belgian Malinois

et al. 2014

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The Belgian Malinois (BM) is an excellent working dog that typically shows a circling behavior when placed in a confined space. Moreover, individuals showing moderate running in circles (one kind of obsessive compulsive behavior) in confined spaces typically show better work performance compared to those without the circling behavior or to those with a serious circling behavior (which can be defined as an obsessive compulsive disorder (OCD)). To determine whether the candidate gene CDH2, Cadherin 2, which is associated with OCD in the Doberman pinscher breed of dogs and in humans, was linked with this behavioral character in the BM, population genetic analyses were performed on a BM population and a natural population of the Chinese indigenous dog (CID). Many genetic signals of balancing selection were detected for one specific region of the CDH2 gene, which suggests that a genomic block, which is included in the CDH2 gene, experienced balancing selection in the BM, and that the CDH2 gene might be associated with the behavioral characteristics of the BM dog (a balance between circling behavior and work performance). Moreover one specific variant, G63913941A, which creates a predicted transcription factor-binding site, may be the key mutation in the CDH2 gene affecting the behavior of BMs by allowing the binding of a transcription factor and increasing CDH2 expression.

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“…Cadherins have been shown to accumulate in synaptic junctions and regulate dendrite development and synapse maturation [50][51][52][53]. Several cadherin family members have been implicated in ASD [16,[54][55][56][57][58][59][60][61][62].…”

Section: Discussionmentioning

confidence: 99%

Identification of CDH11 as an ASD Risk Gene by Matched-gene Co-expression Analysis and Mouse Behavioral Studies

Wang

Jia

et al. 2020

Preprint

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Background: Gene co-expression analysis (GCA) has emerged as an important tool to identify convergent molecular pathways of ASD risk genes. The aim of this study is to identify ASD-relevant genes at the whole-genome level using GCA with consideration of the effect of confounding factors on GCA, including the size, expression level, and guanine-cytosine content of genes. Methods: Pearson’s correlation coefficient was computed to indicate the co-expression of a gene pair based on the BrainSpan human brain transcriptome dataset. Whether a gene is significantly co-expressed with a group of high-confidence ASD risk genes (hcASDs) was determined by statistically comparing the co-expression of this gene with the hcASD gene set to that of this gene with permuted gene sets of matched gene features. This method is referred to as "matched-gene co-expression analysis" (MGCA). Gene ontology (GO) analysis and construction of integrated GO enrichment networks were performed to reveal convergent pathways of co-expressed genes. Behavioral tests were carried out in gene knockout mice. Results: Gene size, mRNA length, mRNA abundance, and guanine-cytosine content were found to affect co-expression profiles of ASD genes. Using the MGCA method, we confirmed the convergence in the developmental expression profiles of hcASDs. MGCA also effectively revealed convergent molecular pathways of ASD risk genes and determined that CDH11, but not CDH9, is associated with ASD. Mouse behavioral studies showed that Cdh11-null mice, but not Cdh9-null mice, have multiple autistic-like behavioral alterations.Limitations: The use of tissue-derived transcriptomes instead of single-cell transcriptomes may have detected coincident expression of some functionally irrelevant genes in different cell types. Some ASD risk genes may have been missed due to the highly stringent statistical standard of MGCA. Another limitation is the relatively small number of animals analyzed in behavioral tests. Conclusions: Results of this study revealed the importance of considering matched gene features in GCA. CDH11 was confirmed to be an important ASD risk gene and Cdh11-null mice were found to be a very useful animal model for investigation of ASD.

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Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

Cited by 42 publications

References 64 publications

The Tourette International Collaborative Genetics (TIC Genetics) study, finding the genes causing Tourette syndrome: objectives and methods

The Tourette International Collaborative Genetics (TIC Genetics) study, finding the genes causing Tourette syndrome: objectives and methods

Balancing Selection on CDH2 May Be Related to the Behavioral Features of the Belgian Malinois

Identification of CDH11 as an ASD Risk Gene by Matched-gene Co-expression Analysis and Mouse Behavioral Studies

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