Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition

Rivero, Olga; Selten, Martijn; Sich, Sarah; Popp, Sandy; Bacmeister, L.; Amendola, Elena; Negwer, Moritz; Schubert, Dirk W.; Proft, Florian; Kiser, Dominik P.; Schmitt, Angelika; Gross, Cornelius; Kolk, Sharon M.; Strekalova, Tatyana; Hove, Daniël L.A. van den; Resink, Thérèse J.; Kasri, Nael Nadif; Lesch, Klaus‐Peter

doi:10.1038/tp.2015.152

Cited by 112 publications

(113 citation statements)

References 79 publications

(105 reference statements)

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“…Not only does our work complement several lines of evidence converging to hippocampal implication in patients with ADHD (Plessen et al, 2006;Posner et al, 2013Posner et al, , 2014Ho et al, 2015;Rivero et al, 2015), but also it extends these findings with respect to functional connectivity. In line with our asymmetry results, Posner and colleagues (Posner et al, 2014) found reduced volume and functional connectivity in the left hippocampus of ADHD children with respect to controls, and associated these modifications with depressive symptoms.…”

Section: Discussionsupporting

confidence: 77%

Inter-hemispherical asymmetry in default-mode functional connectivity and BAIAP2 gene are associated with anger expression in ADHD adults

Hasler

Preti

Meskaldji

et al. 2017

Psychiatry Research: Neuroimaging

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A B S T R A C TAttention deficit hyperactivity disorder (ADHD) is accompanied by resting-state alterations, including abnormal activity, connectivity and asymmetry of the default-mode network (DMN). Concurrently, recent studies suggested a link between ADHD and the presence of polymorphisms within the gene BAIAP2 (i.e., brain-specific angiogenesis inhibitor 1-associated protein 2), known to be differentially expressed in brain hemispheres. The clinical and neuroimaging correlates of this polymorphism are still unknown. We investigated the association between BAIAP2 polymorphisms and DMN functional connectivity (FC) asymmetry as well as behavioral measures in ADHD adults. Resting-state fMRI was acquired from 30 ADHD and 15 healthy adults. For each subject, rs7210438 and rs8079626 within the gene BAIAP2 were genotyped. ADHD severity, impulsiveness and anger were assessed for the ADHD group. Using multivariate analysis of variance, we found that genetic features do have an impact on DMN FC asymmetry. In particular, polymorphism rs8079626 affects medial frontal gyrus and inferior parietal lobule connectivity asymmetry, lower for AA than AG/GG carriers. Further, when combining FC asymmetry and the presence of the rs8079626 variant, we successfully predicted increased externalization of anger in ADHD. In conclusion, a complex interplay between genetic vulnerability and interhemispherical DMN FC asymmetry plays a role in emotion regulation in adult ADHD.

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Section: Discussionsupporting

confidence: 77%

Inter-hemispherical asymmetry in default-mode functional connectivity and BAIAP2 gene are associated with anger expression in ADHD adults

Hasler

Preti

Meskaldji

et al. 2017

Psychiatry Research: Neuroimaging

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“…Each of these observations fit with reported modest human CDH13 associations with ADHD, which is more frequently diagnosed in males (40). However, the sizes of these effects are small, as are the modest effects noted by others in some mnemonic parameters of the conditional knockout mice (20). There are also no effects of constitutive changes in CDH13 on trained performance on the 5-choice serial reaction time task; the same result came from conditional CDH13 knockouts (20).…”

Section: Discussionsupporting

confidence: 67%

“…However, the sizes of these effects are small, as are the modest effects noted by others in some mnemonic parameters of the conditional knockout mice (20). There are also no effects of constitutive changes in CDH13 on trained performance on the 5-choice serial reaction time task; the same result came from conditional CDH13 knockouts (20). The impulsivity phenotype assessed by this test (41) is thus not changed with CDH13 deletion.…”

Section: Discussionsupporting

confidence: 49%

“…Two reports describe different CDH13 knockout mice, one with altered hippocampal function and modest influences on freezing and reversal learning during fear conditioning and Barnes maze tests (19,20). We now report the correlation of human CDH13 genotypes with individual differences in levels of CDH13 mRNAs in postmortem cerebral cortical samples.…”

Section: Methodsmentioning

confidence: 98%

“…CDH13 loxP mice were produced as described (20) and bred with UBC-Cre/ ERT2 mice (Jackson Laboratory; #008085) to obtain homozygous CDH13 loxP/loxP ; UBC-Cre/ERT2 ± and CDH13 loxP/loxP ; UBC-Cre/ERT2 -/-mice.…”

Section: Cadherin 13: Human Cis-regulation and Selectively Altered Admentioning

confidence: 99%

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Cadherin 13: Human cis-Regulation and Selectively Altered Addiction Phenotypes and Cerebral Cortical Dopamine in Knockout Mice

Drgonová

Walther

Hartstein

et al. 2016

Mol Med

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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.

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The role of cadherin genes in five major psychiatric disorders: A literature update

Hawi

Tong

Dark

et al. 2017

American J of Med Genetics Pt B

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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.

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Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition

Cited by 112 publications

References 79 publications

Inter-hemispherical asymmetry in default-mode functional connectivity and BAIAP2 gene are associated with anger expression in ADHD adults

Inter-hemispherical asymmetry in default-mode functional connectivity and BAIAP2 gene are associated with anger expression in ADHD adults

Cadherin 13: Human cis-Regulation and Selectively Altered Addiction Phenotypes and Cerebral Cortical Dopamine in Knockout Mice

The role of cadherin genes in five major psychiatric disorders: A literature update

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