Interactions among genes in the ErbB-Neuregulin signalling network are associated with increased susceptibility to schizophrenia

Benzel, Isabel; Bansal, Aruna T.; Browning, Brian L.; Galwey, Nicholas; Maycox, Peter R.; McGinnis, Ralph; Smart, Devi H.; Clair, David St; Yates, Phillip A.; Purvis, Ian J.

doi:10.1186/1744-9081-3-31

Cited by 119 publications

(109 citation statements)

References 47 publications

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“…There are differences in details in the results between our study and others (Norton et al 2006;Benzel et al 2007), although all studies observed interaction between NRG1 and ERBB4. Norton et al (2006) observed a significant interaction between HAP ICE in NRG1 and IVS12 -15C[T in ERBB4 in a Caucasian sample.…”

Section: Discussioncontrasting

confidence: 54%

“…The IVS12 -15C[T showed no polymorphism in a Japanese population, and differences in allele and haplotype frequencies of NRG1 are remarkable between the populations (Gardner et al 2006). The difference in ethnicity or selection of SNPs may account for the difference between our result and that in Benzel et al (2007), which suggested 45 pair-wise SNP interactions between NRG1 and ERBB4 in Caucasian.…”

Section: Discussioncontrasting

confidence: 37%

“…Two studies have investigated the association between ERBB3 and schizophrenia using a Japanese sample, although no association was observed (Kanazawa et al 2007;Watanabe et al 2007). Conversely, four studies provided evidence for an association between ERBB4 and schizophrenia (Nicodemus et al 2006;Norton et al 2006;Silberberg et al 2006;Benzel et al 2007), two of which observed that interaction between NRG1 and ERBB4 increased susceptibility for schizophrenia (Norton et al 2006;Benzel et al 2007). However, no other study to date has examined the interaction between the two genes.…”

Section: Introductionmentioning

confidence: 99%

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Association and interaction analyses of NRG1 and ERBB4 genes with schizophrenia in a Japanese population

et al. 2008

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Neuregulin 1 (NRG1) is one of the most promising candidate genes for schizophrenia. A number of replication studies have been conducted, although the results were inconsistent and no susceptible variant has yet been identified. The inconsistency might be attributed to the ethnic difference in allele and haplotype frequencies. However, it is equally possible that one or more genes interacting with NRG1 may also be implicated in schizophrenia and attribute to the inconsistency. To test the hypothesis, we conducted an interaction analysis between NRG1 and one of its receptor's (ERBB4) polymorphisms as well as the association analysis of the two genes associated with schizophrenia in Japanese. We observed no significant difference between patients and controls in allele frequencies or genotypic distributions of the 18 polymorphisms of the genes. The permutation test showed no significant differences in estimated haplotype frequencies between patients and controls, including the haplotype HAP ICE . In the interaction analysis, significant interaction was observed between rs2919381 in NRG1 and rs7560730 in ERBB4 (P = 0.047, corrected). Thus, our results suggest the possibility that interaction between variants in NRG1 and ERBB4 might contribute to susceptibility for schizophrenia in a Japanese population. Further investigation may be necessary to confirm our results.

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Section: Discussioncontrasting

confidence: 54%

Section: Discussioncontrasting

confidence: 37%

Section: Introductionmentioning

confidence: 99%

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Association and interaction analyses of NRG1 and ERBB4 genes with schizophrenia in a Japanese population

et al. 2008

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“…The chromosome 10q22-q23 locus also shows linkage to schizophrenia in Ashkenazi Jewish and Han Chinese populations (2,3), and noncoding genetic variation in NRG3 has been identified as a putative risk factor for schizophrenia and related neuropsychiatric disorders (4)(5)(6)(7). Genetic association studies have also identified multiple genes and epistatic locus interactions (8) within the NRG-ErbB signaling pathway that increase risk for schizophrenia, including NRG3, NRG1, ErbB4, and AKT1, suggesting a pathogenic gene network.…”

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confidence: 99%

Common genetic variation in Neuregulin 3 ( NRG3 ) influences risk for schizophrenia and impacts NRG3 expression in human brain

Kao

Wang

Kleinman

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

122

133

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Structural and polymorphic variations in Neuregulin 3 (NRG3), 10q22-23 are associated with a broad spectrum of neurodevelopmental disorders including developmental delay, cognitive impairment, autism, and schizophrenia. NRG3 is a member of the neuregulin family of EGF proteins and a ligand for the ErbB4 receptor tyrosine kinase that plays pleotropic roles in neurodevelopment. Several genes in the NRG-ErbB signaling pathway including NRG1 and ErbB4 have been implicated in genetic predisposition to schizophrenia. Previous fine mapping of the 10q22-23 locus in schizophrenia identified genomewide significant association between delusion severity and polymorphisms in intron 1 of NRG3 (rs10883866, rs10748842, and rs6584400). The biological mechanisms remain unknown. We identified significant association of these SNPs with increased risk for schizophrenia in 350 families with an affected offspring and confirmed association to patient delusion and positive symptom severity. Molecular cloning and cDNA sequencing in human brain revealed that NRG3 undergoes complex splicing, giving rise to multiple structurally distinct isoforms. RNA expression profiling of these isoforms in the prefrontal cortex of 400 individuals revealed that NRG3 expression is developmentally regulated and pathologically increased in schizophrenia. Moreover, we show that rs10748842 lies within a DNA ultraconserved element and homedomain and strongly predicts brain expression of NRG3 isoforms that contain a unique developmentally regulated 5′ exon (P = 1.097E −12 to 1.445E −15 ). Our observations strengthen the evidence that NRG3 is a schizophrenia susceptibility gene, provide quantitative insight into NRG3 transcription traits in the human brain, and reveal a probable mechanistic basis for disease association.clinical genetics | development | ErbB4 | neuregulin | NRG1

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“…Functional NRG1 receptors therefore consist of ErbB4 homodimers, or of heterodimers between ErbB2, ErbB3 and ErbB4 (1). NRG1 and its receptors are expressed in the CNS and the NRG1, ErbB2, and ErbB4 genes are candidate susceptibility genes for schizophrenia (1,2). In the central nervous system (CNS), NRG1 is thought to regulate the differentiation of radial glia and neurons, myelination, neuronal migration and synaptic function (1).…”

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confidence: 99%

Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system

Barros

Calabrese

Chamero

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

185

174

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Neuregulin-1 (NRG1) and its ErbB2/B4 receptors are encoded by candidate susceptibility genes for schizophrenia, yet the essential functions of NRG1 signaling in the CNS are still unclear. Using CRE/LOX technology, we have inactivated ErbB2/B4-mediated NRG1 signaling specifically in the CNS. In contrast to expectations, cell layers in the cerebral cortex, hippocampus, and cerebellum develop normally in the mutant mice. Instead, loss of ErbB2/B4 impairs dendritic spine maturation and perturbs interactions of postsynaptic scaffold proteins with glutamate receptors. Conversely, increased NRG1 levels promote spine maturation. ErbB2/B4-deficient mice show increased aggression and reduced prepulse inhibition. Treatment with the antipsychotic drug clozapine reverses the behavioral and spine defects. We conclude that ErbB2/B4-mediated NRG1 signaling modulates dendritic spine maturation, and that defects at glutamatergic synapses likely contribute to the behavioral abnormalities in ErbB2/ B4-deficient mice.cerebral cortex ͉ dendritic spines ͉ migration ͉ neuregulin ͉ schizophrenia N RG1 activates receptor tyrosine kinases consisting of dimers formed by ErbB2, ErbB3, and ErbB4. Both ErbB3 and ErbB4 bind NRG1, whereas ErbB2 and ErbB4 have intrinsic tyrosine kinase activity. Functional NRG1 receptors therefore consist of ErbB4 homodimers, or of heterodimers between ErbB2, ErbB3 and ErbB4 (1). NRG1 and its receptors are expressed in the CNS and the NRG1, ErbB2, and ErbB4 genes are candidate susceptibility genes for schizophrenia (1, 2). In the central nervous system (CNS), NRG1 is thought to regulate the differentiation of radial glia and neurons, myelination, neuronal migration and synaptic function (1). However, mice with targeted deletions of NRG1, ErbB2 and ErbB4 die during embryogenesis, whereas mice lacking ErbB3 die perinatally (3-6). Thus, our knowledge of NRG1-ErbB functions in the CNS has been derived from studies using cultured cells, dominantnegative ErbB receptors, and mice partially defective in NRG1 signaling (1). No animal model lacking all NRG1 signaling specifically in the CNS has been described. We have therefore engineered ErbB2/B4-CNSko mice that lack both ErbB2 and ErbB4 (the only ErbBs with intrinsic tyrosine kinase activity) in the CNS. Surprisingly, the mutant mice show no defects in brain morphology and in the layered structure of the cerebral cortex, hippocampus, and cerebellum. Instead, the maturation of dendritic spines is affected. ErbB2/B4-deficient mice also display behavioral abnormalities that have been associated with schizophrenia-like symptoms. Clozapine treatment reverses behavioral and spine defects, indicating that perturbation of glutamatergic synapses might contribute to the behavioral abnormalities. Interestingly, reduced spine density has been observed in the brain of schizophrenia patients (7), suggesting that defects in spine maturation may constitute a risk factor for the development of schizophrenia. ResultsNormal Cortical Development and Glial-Guided Migration. To inactivate NR...

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Interactions among genes in the ErbB-Neuregulin signalling network are associated with increased susceptibility to schizophrenia

Cited by 119 publications

References 47 publications

Association and interaction analyses of NRG1 and ERBB4 genes with schizophrenia in a Japanese population

Association and interaction analyses of NRG1 and ERBB4 genes with schizophrenia in a Japanese population

Common genetic variation in Neuregulin 3 ( NRG3 ) influences risk for schizophrenia and impacts NRG3 expression in human brain

Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system

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