| 1 | Exp. Cell Res. 2003 Mar 284: 14-30 |
|---|---|
| PMID | 12648463 |
| Title | Neuregulins: functions, forms, and signaling strategies. |
| Abstract | The neuregulins (NRGs) are cell-cell signaling proteins that are ligands for receptor tyrosine kinases of the ErbB family. The neuregulin family of genes has four members: NRG1, NRG2, NRG3, and NRG4. Relatively little is known about the biological functions of the NRG2, 3, and 4 proteins, and they are considered in this review only briefly. The NRG1 proteins play essential roles in the nervous system, heart, and breast. There is also evidence for involvement of NRG signaling in the development and function of several other organ systems, and in human disease, including the pathogenesis of schizophrenia and breast cancer. There are many NRG1 isoforms, raising the question "Why so many neuregulins?" Study of mice with targeted mutations ("knockout mice") has demonstrated that isoforms differing in their N-terminal region or in their epidermal growth factor (EGF)-like domain differ in their in vivo functions. These differences in function might arise because of differences in expression pattern or might reflect differences in intrinsic biological characteristics. While differences in expression pattern certainly contribute to the observed differences in in vivo functions, there are also marked differences in intrinsic characteristics that may tailor isoforms for specific signaling requirements, a theme that will be emphasized in this review. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Adv Anat Embryol Cell Biol 2007 -1 190: 1-65 |
| PMID | 17432114 |
| Title | The neuregulin-I/ErbB signaling system in development and disease. |
| Abstract | Neuregulins (NRGs) comprise a large family of EGF-like signaling molecules involved in cell-cell communication during development and disease. The neuregulin family of ligands has four members: NRG1, NRG2, NRG3, and NRG4. Relatively little is known about the biological functions of the NRG2, 3, and 4 proteins. In contrast, the NRG1 proteins have been demonstrated to play important roles during the development of the nervous system, heart, and mammary glands. For example, NRG1 has essential functions in the development of neural crest cells and some of their major derivatives, like Schwann cells and sympathetic neurons. NRG1 controls the trabeculation of the myocardial musculature and the ductal differentiation of the mammary epithelium. Moreover, there is emerging evidence for the involvement of NRG signals in the development and function of several other organ systems, and in human disease, including breast cancer and schizophrenia. Many different isoforms of the Neuregulin-1 gene are synthesized. Such isoforms differ in their tissue-specific expression patterns and their biological activities, thereby contributing to the great diversity of the in vivo functions of NRG1. Neuregulins transmit their signals to target cells by interacting with transmembrane tyrosine kinase receptors of the ErbB family. This family includes four members, the epidermal growth factor receptor (EGF-R, ErbB1, ErbB2, ErbB3, and ErbB4). Receptor-ligand interaction induces the heterodimerization of receptor monomers, which in turn results in the activation of intracellular signaling cascades and the induction of cellular responses including proliferation, migration, differentiation, and survival or apoptosis. In vivo, functional NRG1 receptors are heterodimers composed of ErbB2 with either an ErbB3, or ErbB4 molecule. The tissue-specific distribution of the different receptor types further contributes to the diversity and specificity of the biological functions of this signaling pathway. It is a typical feature of the Neuregulin-1/ErbB signaling pathway to control sequential steps during the development of a particular organ system. For example, this pathway functions in early precursor proliferation, maturation, as well as in the myelination of Schwann cells. The systematic analysis of genetic models that have been established by the help of conventional as well as conditional gene targeting strategies in mice was instrumental for the uncovering of the multitude of biological functions of this signaling system. In this review the basic biology of the Neuregulin-1/ErbB system and how it relates to the in vivo functions were discussed with special emphasis to transgenic techniques in mice. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Behav Brain Funct 2007 -1 3: 31 |
| PMID | 17598910 |
| Title | Interactions among genes in the ErbB-Neuregulin signalling network are associated with increased susceptibility to schizophrenia. |
| Abstract | Evidence of genetic association between the NRG1 (Neuregulin-1) gene and schizophrenia is now well-documented. Furthermore, several recent reports suggest association between schizophrenia and single-nucleotide polymorphisms (SNPs) in ERBB4, one of the receptors for Neuregulin-1. In this study, we have extended the previously published associations by investigating the involvement of all eight genes from the ERBB and NRG families for association with schizophrenia. Eight genes from the ERBB and NRG families were tested for association to schizophrenia using a collection of 396 cases and 1,342 blood bank controls ascertained from Aberdeen, UK. A total of 365 SNPs were tested. Association testing of both alleles and genotypes was carried out using the fast Fisher's Exact Test (FET). To understand better the nature of the associations, all pairs of SNPs separated by >or= 0.5 cM with at least nominal evidence of association (P < 0.10) were tested for evidence of pairwise interaction by logistic regression analysis. 42 out of 365 tested SNPs in the eight genes from the ERBB and NRG gene families were significantly associated with schizophrenia (P < 0.05). Associated SNPs were located in ERBB4 and NRG1, confirming earlier reports. However, novel associations were also seen in NRG2, NRG3 and EGFR. In pairwise interaction tests, clear evidence of gene-gene interaction was detected for NRG1-NRG2, NRG1-NRG3 and EGFR-NRG2, and suggestive evidence was also seen for ERBB4-NRG1, ERBB4-NRG2, ERBB4-NRG3 and ERBB4-ERBB2. Evidence of intragenic interaction was seen for SNPs in ERBB4. These new findings suggest that observed associations between NRG1 and schizophrenia may be mediated through functional interaction not just with ERBB4, but with other members of the NRG and ERBB families. There is evidence that genetic interaction among these loci may increase susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Biol. Psychiatry 2008 Dec 64: 1093-6 |
| PMID | 18708184 |
| Title | Neuregulin 3 genetic variations and susceptibility to schizophrenia in a Chinese population. |
| Abstract | The study investigated the possible association of NRG3 gene and schizophrenia in a Han Chinese population. Of a total of 1345, 270 unrelated schizophrenia inpatients, 235 normal control subjects, and 280 nuclear families (trios) with schizophrenia probands were studied. Nine single nucleotide polymorphisms (SNPs) spanning intron 1 to exon 9 of the NRG3 gene were analyzed, starting with the case-control samples. The SNPs showing significant association with schizophrenia in the case-control samples were subsequently studied in the independent trio samples with family-based association analysis. In case-control samples, two SNPs (rs1937970 and rs677221) showed significant genotypic and allelic association with schizophrenia (all p < .05) with rs677221-C being the risk allele for schizophrenia (uncorrected p = .001, odds ratio = 1.439, 95% confidence interval = 1.115-1.858). Haplotypes GC constructed by the two SNPs was also significantly associated with schizophrenia (permutation p value = .0047). In the independent trio samples, rs1937970-A and rs677221-G consistently showed significant under-transmission to schizophrenic offspring (unadjusted p = .003 and p = .004, respectively). In the haplotype-transmission disequilibrium test (TDT) for allelic combination of rs1937970-rs677221, significant under-transmission for haplotype AG (uncorrected p = .006) and over-transmission for haplotype GC (uncorrected p = .004) to the affected schizophrenia offspring were observed. The result supports that the NRG3 gene is a susceptibility gene for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Biol. Psychiatry 2008 Dec 64: 1093-6 |
| PMID | 18708184 |
| Title | Neuregulin 3 genetic variations and susceptibility to schizophrenia in a Chinese population. |
| Abstract | The study investigated the possible association of NRG3 gene and schizophrenia in a Han Chinese population. Of a total of 1345, 270 unrelated schizophrenia inpatients, 235 normal control subjects, and 280 nuclear families (trios) with schizophrenia probands were studied. Nine single nucleotide polymorphisms (SNPs) spanning intron 1 to exon 9 of the NRG3 gene were analyzed, starting with the case-control samples. The SNPs showing significant association with schizophrenia in the case-control samples were subsequently studied in the independent trio samples with family-based association analysis. In case-control samples, two SNPs (rs1937970 and rs677221) showed significant genotypic and allelic association with schizophrenia (all p < .05) with rs677221-C being the risk allele for schizophrenia (uncorrected p = .001, odds ratio = 1.439, 95% confidence interval = 1.115-1.858). Haplotypes GC constructed by the two SNPs was also significantly associated with schizophrenia (permutation p value = .0047). In the independent trio samples, rs1937970-A and rs677221-G consistently showed significant under-transmission to schizophrenic offspring (unadjusted p = .003 and p = .004, respectively). In the haplotype-transmission disequilibrium test (TDT) for allelic combination of rs1937970-rs677221, significant under-transmission for haplotype AG (uncorrected p = .006) and over-transmission for haplotype GC (uncorrected p = .004) to the affected schizophrenia offspring were observed. The result supports that the NRG3 gene is a susceptibility gene for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Neurosci. Lett. 2009 Nov 466: 27-9 |
| PMID | 19765633 |
| Title | Levels of neuregulin 1 and 3 proteins in Brodmann's area 46 from subjects with schizophrenia and bipolar disorder. |
| Abstract | Neuregulin (NRG) 1Ialpha and NRG3 proteins levels were measured in Brodmann's area 46 from 20 subjects with schizophrenia, 8 subjects with bipolar 1 disorder and 20 age-sex matched control subjects. Protein levels of both NRG1Ialpha and NRG3 were unchanged in both psychiatric illnesses. These data suggest any change in NRG1Ialpha and NRG3 expression in schizophrenia or bipolar 1 disorder do not result in changes levels in levels of those proteins Brodmann's area 46. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Am. J. Hum. Genet. 2009 Jan 84: 21-34 |
| PMID | 19118813 |
| Title | Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia. |
| Abstract | Linkage studies have implicated 10q22-q23 as a schizophrenia (SZ) susceptibility locus in Ashkenazi Jewish (AJ) and Han Chinese from Taiwan populations. To further explore our previous linkage signal in the AJ population (NPL score: 4.27, empirical p = 2 x 10(-5)), we performed a peakwide association fine mapping study by using 1414 SNPs across approximately 12.5 Mb in 10q22-q23. We genotyped 1515 AJ individuals, including 285 parent-child trios, 173 unrelated cases, and 487 unrelated controls. We analyzed the binary diagnostic phenotype of SZ and 9 heritable quantitative traits derived from a principal components factor analysis of 73 items from our consensus diagnostic ratings and direct assessment interviews. Although no marker withstood multiple test correction for association with the binary SZ phenotype, we found strong evidence of association by using the "delusion" factor as the quantitative trait at three SNPs (rs10883866, rs10748842, and rs6584400) located in a 13 kb interval in intron 1 of Neuregulin 3 (NRG3). Our best p value from family-based association analysis was 7.26 x 10(-7). We replicated this association in the collection of 173 unrelated AJ cases (p = 1.55 x 10(-2)), with a combined p value of 2.30 x 10(-7). After performing 10,000 permutations of each of the phenotypes, we estimated the empirical study-wide significance across all 9 factors (90,000 permutations) to be p = 2.7 x 10(-3). NRG3 is primarily expressed in the central nervous system and is one of three paralogs of NRG1, a gene strongly implicated in SZ. These biological properties together with our linkage and association results strongly support NRG3 as a gene involved in SZ. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Mol. Psychiatry 2009 Nov 14: 1024-31 |
| PMID | 18521091 |
| Title | Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia. |
| Abstract | Administration of certain drugs (for example, antiarrhythmics, antihistamines, antibiotics, antipsychotics) may occasionally affect myocardial repolarization and cause prolongation of the QT interval. We performed a whole genome association study of drug-induced QT prolongation after 14 days of treatment in a phase 3 clinical trial evaluating the efficacy, safety and tolerability of a novel atypical antipsychotic, iloperidone, in patients with schizophrenia. We identified DNA polymorphisms associated with QT prolongation in six loci, including the CERKL and SLCO3A1 genes. Each single nucleotide polymorphism (SNP) defined two genotype groups associated with a low mean QT change (ranging from -0.69 to 5.67 ms depending on the SNP) or a higher mean QT prolongation (ranging from 14.16 to 17.81 ms). The CERKL protein is thought to be part of the ceramide pathway, which regulates currents conducted by various potassium channels, including the hERG channel. It is well established that inhibition of the hERG channel can prolong the QT interval. SLCO3A1 is thought to play a role in the translocation of prostaglandins, which have known cardioprotective properties, including the prevention of torsades de pointes. Our findings also point to genes involved in myocardial infarction (PALLD), cardiac structure and function (BRUNOL4) and cardiac development (NRG3). Results of this pharmacogenomic study provide new insight into the clinical response to iloperidone, developed with the goal of directing therapy to those patients with the optimal benefit/risk ratio. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Proc. Natl. Acad. Sci. U.S.A. 2010 Aug 107: 15619-24 |
| PMID | 20713722 |
| Title | Common genetic variation in Neuregulin 3 (NRG3) influences risk for schizophrenia and impacts NRG3 expression in human brain. |
| Abstract | 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 genome-wide 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. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Proc. Natl. Acad. Sci. U.S.A. 2010 Mar 107: 5622-7 |
| PMID | 20212127 |
| Title | Disrupted-in-Schizophrenia-1 expression is regulated by beta-site amyloid precursor protein cleaving enzyme-1-neuregulin cascade. |
| Abstract | Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia-1 (DISC1) are promising susceptibility factors for schizophrenia. Both are multifunctional proteins with roles in a variety of neurodevelopmental processes, including progenitor cell proliferation, migration, and differentiation. Here, we provide evidence linking these factors together in a single pathway, which is mediated by ErbB receptors and PI3K/Akt. We show that signaling by NRG1 and NRG2, but not NRG3, increase expression of an isoform of DISC1 in vitro. Receptors ErbB2 and ErbB3, but not ErbB4, are responsible for transducing this effect, and PI3K/Akt signaling is also required. In NRG1 knockout mice, this DISC1 isoform is selectively reduced during neurodevelopment. Furthermore, a similar decrease in DISC1 expression is seen in beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) knockout mice, in which NRG1/Akt signaling is reportedly impaired. In contrast to neuronal DISC1 that was reported and characterized, expression of DISC1 in other types of cells in the brain has not been addressed. Here we demonstrate that DISC1, like NRG and ErbB proteins, is expressed in neurons, astrocytes, oligodendrocytes, microglia, and radial progenitors. These findings may connect NRG1, ErbBs, Akt, and DISC1 in a common pathway, which may regulate neurodevelopment and contribute to susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Mol. Psychiatry 2011 Aug 16: 860-6 |
| PMID | 20548296 |
| Title | Neuregulin 3 (NRG3) as a susceptibility gene in a schizophrenia subtype with florid delusions and relatively spared cognition. |
| Abstract | Linkage of 10q22-q23 to schizophrenia and the recently reported association of Neuregulin 3 (NRG3) polymorphisms with high 'delusion factor' scores led us to attempt replication and further refinement of these findings in a sample of 411 schizophrenic patients and 223 nonpsychiatric control subjects. Using quantitative cognitive traits, patients were grouped into a cluster with pervasive cognitive deficit (CD) and a cluster with relatively spared cognition (CS). We found a significant association between rs6584400 and schizophrenia, with a trend for rs10883866. Post hoc analysis revealed that this result was mainly due to the CS cluster, characterized by elevated scores on Schneiderian first-rank symptoms, salience of complex delusions and positive thought disorder--thus closely related to the 'delusion factor'. In addition, both rs6584400 and rs10883866 were associated with the degraded-stimulus continuous performance task in which 'risk' alleles were associated with better than average performance in patients and worse performance in controls. This suggests that NRG3 may be modulating early attentional processes for perceptual sensitivity and vigilance, with opposite effects in affected individuals and healthy controls. The two single-nucleotide polymorphisms are in close proximity to the alternative first exons of the NRG3-a, -b and -d isoforms, of which the human brain-specific NRG-b appears to be the most interesting candidate. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Mol. Psychiatry 2011 Aug 16: 860-6 |
| PMID | 20548296 |
| Title | Neuregulin 3 (NRG3) as a susceptibility gene in a schizophrenia subtype with florid delusions and relatively spared cognition. |
| Abstract | Linkage of 10q22-q23 to schizophrenia and the recently reported association of Neuregulin 3 (NRG3) polymorphisms with high 'delusion factor' scores led us to attempt replication and further refinement of these findings in a sample of 411 schizophrenic patients and 223 nonpsychiatric control subjects. Using quantitative cognitive traits, patients were grouped into a cluster with pervasive cognitive deficit (CD) and a cluster with relatively spared cognition (CS). We found a significant association between rs6584400 and schizophrenia, with a trend for rs10883866. Post hoc analysis revealed that this result was mainly due to the CS cluster, characterized by elevated scores on Schneiderian first-rank symptoms, salience of complex delusions and positive thought disorder--thus closely related to the 'delusion factor'. In addition, both rs6584400 and rs10883866 were associated with the degraded-stimulus continuous performance task in which 'risk' alleles were associated with better than average performance in patients and worse performance in controls. This suggests that NRG3 may be modulating early attentional processes for perceptual sensitivity and vigilance, with opposite effects in affected individuals and healthy controls. The two single-nucleotide polymorphisms are in close proximity to the alternative first exons of the NRG3-a, -b and -d isoforms, of which the human brain-specific NRG-b appears to be the most interesting candidate. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | Genes Brain Behav. 2011 Nov 10: 828-33 |
| PMID | 21762460 |
| Title | Neuregulin 3 does not confer risk for schizophrenia and smooth pursuit eye movement abnormality in a Korean population. |
| Abstract | Located on chromosome 10q22-q23, the human neuregulin3 (NRG3) is considered to be a strong positional and functional candidate gene for schizophrenia pathogenesis. Several case-control studies examining the association of polymorphisms in NRG3 with schizophrenia and/or related traits such as delusion have been reported recently in cohorts of Han Chinese, Ashkenazi Jews, Australians and white Americans of Western European ancestry. Thus, this study aimed to comprehensively investigate the association of NRG3 genetic variations with the risk of schizophrenia and smooth pursuit eye movement (SPEM) abnormality in a Korean population. Using TaqMan assay, six single-nucleotide polymorphisms (SNPs) in the intronic region of NRG3 were genotyped and two major haplotypes were identified in 435 patients with schizophrenia as cases and 393 unrelated healthy individuals as controls. A total of 113 schizophrenia patients underwent an eye tracking task, and degree of SPEM abnormality was measured using the logarithmic values of the signal/noise (Ln S/N) ratio. Differences in frequency distributions were analyzed using logistic and regression models following various modes of genetic inheritance and controlling for age and sex as covariates. Subsequent analysis revealed that the frequency distributions of NRG3 polymorphisms and haplotypes were similar between schizophrenia patients and healthy controls of Korean ethnicity. Furthermore, no significant differences were observed between the genetic variants tested for SPEM abnormality. By elucidating a lack of association in a Korean population, findings from this study may contribute to the understanding of the genetic etiology focusing on the role of NRG3 in schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 14 | PLoS ONE 2012 -1 7: e44017 |
| PMID | 22952857 |
| Title | Allele-biased expression in differentiating human neurons: implications for neuropsychiatric disorders. |
| Abstract | Stochastic processes and imprinting, along with genetic factors, lead to monoallelic or allele-biased gene expression. Stochastic monoallelic expression fine-tunes information processing in immune cells and the olfactory system, and imprinting plays an important role in development. Recent studies suggest that both stochastic events and imprinting may be more widespread than previously considered. We are interested in allele-biased gene expression occurring in the brain because parent-of-origin effects suggestive of imprinting appear to play a role in the transmission of schizophrenia (SZ) and autism spectrum disorders (ASD) in some families. In addition, allele-biased expression could help explain monozygotic (MZ) twin discordance and reduced penetrance. The ability to study allele-biased expression in human neurons has been transformed with the advent of induced pluripotent stem cell (iPSC) technology and next generation sequencing. Using transcriptome sequencing (RNA-Seq) we identified 801 genes in differentiating neurons that were expressed in an allele-biased manner. These included a number of putative SZ and ASD candidates, such as A2BP1 (RBFOX1), ERBB4, NLGN4X, NRG1, NRG3, NRXN1, and NLGN1. Overall, there was a modest enrichment for SZ and ASD candidate genes among those that showed evidence for allele-biased expression (chi-square, p = 0.02). In addition to helping explain MZ twin discordance and reduced penetrance, the capacity to group many candidate genes affecting a variety of molecular and cellular pathways under a common regulatory process - allele-biased expression - could have therapeutic implications. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 15 | Evol. Bioinform. Online 2013 -1 9: 29-42 |
| PMID | 23423242 |
| Title | A proximity-based method to identify genomic regions correlated with a continuously varying environmental variable. |
| Abstract | Knowledge of markers in the human genome which show spatial patterns and display extreme correlation with different environmental determinants play an important role in understanding the factors which affect the biological evolution of our species. We used the genotype data of more than half a million single nucleotide polymorphisms (SNPs) from the data set Human Genome Diversity Panel (HGDP-CEPH -CEPH) and we calculated Spearman's correlation between absolute latitude and one of the two allele frequencies of each SNP. We selected SNPs with a correlation coefficient within the upper 1% tail of the distribution. We then used a criterion of proximity between significant variants to focus on DNA regions showing a continuous signal over a portion of the genome. Based on external information and genome annotations, we demonstrated that most regions with the strongest signals also have biological relevance. We believe this proximity requirement adds an edge to our novel method compared to the existing literature, highlighting several genes (for example DTNB, DOT1L, TPCN2, RELN, MSRA, NRG3) related to body size or shape, human height, hair color, and schizophrenia. Our approach can be applied generally to any measure of association between polymorphic frequencies and continuously varying environmental variables. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 16 | Psychiatry Res 2013 Feb 205: 279-81 |
| PMID | 22981155 |
| Title | No genetic evidence for Neuregulin 3 conferring risk of schizophrenia in the Chinese population. |
| Abstract | We genotyped 13 single nucleotide polymorphisms (SNPs) within Neuregulin 3 (NRG3) to investigate the association between NRG3 and schizophrenia in 488 patients and 506 controls in Northwest China. No association was detected either in SNPs or in haplotypes. Our study provided no evidence that NRG3 confers a risk of schizophrenia susceptibility in the Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 17 | Transl Psychiatry 2013 -1 3: e264 |
| PMID | 23715299 |
| Title | Multiple variants aggregate in the neuregulin signaling pathway in a subset of schizophrenia patients. |
| Abstract | Despite the strongly held view that schizophrenia (SZ) shows substantial genetic heterogeneity, pathway heterogeneity, as seen in cancer where different pathways are affected in similar tumors, has not been explored. We explore this possibility in a case-only study of the neuregulin signaling pathway (NSP), which has been prominently implicated in SZ and for which there is detailed knowledge on the ligand- and receptor-processing steps through ?- and ?-secretase cleavage. We hypothesize that more than one damaging variants in the NSP genes might be necessary to cause disease, leading to an apparent clustering of such variants in only the few patients with affected NSP. We analyze linkage and next-generation sequencing results for the genes encoding components of the pathway, including NRG1, NRG3, ERBB4, ?-secretase and the ?-secretase complex. We find multiple independent examples of supporting evidence for this hypothesis: (i) increased linkage scores over NSP genes, (ii) multiple positive interlocus correlations of linkage scores across families suggesting each family is linked to either many or none of the genes, (iii) aggregation of predicted damaging variants in a subset of individuals and (iv) significant phenotypic differences of the subset of patients carrying such variants. Collectively, our data strongly support the hypothesis that the NSP is affected by multiple damaging variants in a subset of phenotypically distinct patients. On the basis of this, we propose a general model of pathway heterogeneity in SZ, which, in part, may explain its phenotypic variability and genetic complexity. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 18 | Int. J. Neuropsychopharmacol. 2013 Apr 16: 549-56 |
| PMID | 22831755 |
| Title | Neuregulin 3 is associated with attention deficits in schizophrenia and bipolar disorder. |
| Abstract | Linkage and fine mapping studies have established that the neuregulin 3 gene (NRG3) is a susceptibility locus for schizophrenia. Association studies of this disorder have implicated NRG3 variants in both psychotic symptoms and attention performance. Psychotic symptoms and cognitive deficits are also frequent features of bipolar disorder. The aims of the present study were to extend analysis of the association between NRG3 and psychotic symptoms and attention in schizophrenia and to determine whether these associations also apply to bipolar disorder. A total of 358 patients with schizophrenia and 111 patients with bipolar disorder were included. Psychotic symptoms were evaluated using the Operational Criteria Checklist for Psychotic Illness (OPCRIT) and attention performance was assessed using the Trail Making Test (TMT). Symptoms and performance scores were then tested for association with the NRG3 variant rs6584400. A significant association was found between the number of rs6584400 minor alleles and the total OPCRIT score for psychotic symptoms in patients with schizophrenia. Moreover, in both schizophrenia and bipolar disorder patients, minor allele carriers of rs6584400 outperformed homozygous major allele carriers in the TMT. The results suggest that rs6584400 is associated with psychotic symptoms and attention performance in schizophrenia. The finding of a significant association between rs6584400 and attention performance in bipolar disorder supports the hypothesis that this NRG3 variant confers genetic susceptibility to cognitive deficits in both schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 19 | PLoS ONE 2014 -1 9: e104172 |
| PMID | 25093331 |
| Title | Transient overexposure of neuregulin 3 during early postnatal development impacts selective behaviors in adulthood. |
| Abstract | Neuregulin 3 (NRG3), a specific ligand for ErbB4 and a neuronal-enriched neurotrophin is implicated in the genetic predisposition to a broad spectrum of neurodevelopmental, neurocognitive and neuropsychiatric disorders, including Alzheimer's disease, autism and schizophrenia. Genetic studies in schizophrenia demonstrate that risk variants in NRG3 are associated with cognitive and psychotic symptom severity, accompanied by increased expression of prefrontal cortical NRG3. Despite our expanding knowledge of genetic involvement of NRG3 in neurological disorders, little is known about the neurodevelopmental mechanisms of risk. Here we exploited the fact that a paralog of NRG3, NRG1, readily penetrates the murine blood brain barrier (BBB). In this study we synthesized the bioactive epidermal growth factor (EGF) domain of NRG3, and using previously validated in-vivo peripheral injection methodologies in neonatal mice, demonstrate that NRG3 successfully crosses the BBB, where it activates its receptor ErbB4 and downstream Akt signaling at levels of bioactivity comparable to NRG1. To determine the impact of NRG3 overexpression during one critical developmental window, C57BL/6 male mice were subcutaneously injected daily with NRG1-EGF, NRG3-EGF or vehicle from postnatal days 2-10. Mice were tested in adulthood using a comprehensive battery of behavioral tasks relevant to neurocognitive and psychiatric disorders. In agreement with previous studies, developmental overexposure to NRG1 induced multiple non-CNS mediated peripheral effects as well as severely disrupting performance of prepulse inhibition of the startle response. In contrast, NRG3 had no effect on any peripheral measures investigated or sensorimotor gating. Specifically, developmental NRG3 overexposure produced an anxiogenic-like phenotype and deficits in social behavior in adulthood. These results provide primary data to support a role for NRG3 in brain development and function, which appears to be distinct from its paralog NRG1. Furthermore we demonstrate how perturbations in NRG3 expression at distinct developmental stages may contribute to the neurological deficits observed in brain disorders such as schizophrenia and autism. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 20 | Biol. Psychiatry 2014 Oct 76: 648-55 |
| PMID | 24703509 |
| Title | Neuregulin-3 in the mouse medial prefrontal cortex regulates impulsive action. |
| Abstract | A deficit in impulse control is a prominent, heritable symptom in several psychiatric disorders, such as addiction, attention-deficit/hyperactivity disorder, and schizophrenia. Here, we aimed to identify genes regulating impulsivity, specifically of impulsive action, in mice. Using the widely used 5-choice serial reaction time task, we measured impulsive action in 1) a panel of 41 BXD recombinant inbred strains of mice (n = 13.7 ± .8 per strain; n = 654 total) to detect underlying genetic loci; 2) congenic mice (n = 23) to replicate the identified locus; 3) mice overexpressing the NRG3 candidate gene in the medial prefrontal cortex (n = 21); and 4) a NRG3 loss-of-function mutant (n = 59) to functionally implicate the NRG3 candidate gene in impulsivity. Genetic mapping of impulsive action in the BXD panel identified a locus on chromosome 14 (34.5-41.4 Mb), syntenic with the human 10q22-q23 schizophrenia-susceptibility locus. Congenic mice carrying the impulsivity locus (Impu1) confirmed its influence on impulsive action. Increased impulsivity was associated with increased NRG3 gene expression in the medial prefrontal cortex (mPFC). Viral overexpression of NRG3 in the mPFC increased impulsivity, whereas a constitutive NRG3 loss-of-function mutation decreased it. The causal relation between NRG3 expression in the mPFC and level of impulsive action shown here provides a mechanism by which polymorphism in NRG3 in humans contributes to a specific cognitive deficit seen in several psychiatric diseases, such as addiction, attention-deficit/hyperactivity disorder, and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 21 | J. Neurosci. 2014 Jan 34: 1051-6 |
| PMID | 24431462 |
| Title | Effects of neuregulin 3 genotype on human prefrontal cortex physiology. |
| Abstract | The neuregulin 3 gene (NRG3) plays pleiotropic roles in neurodevelopment and is a putative susceptibility locus for schizophrenia. Specifically, the T allele of NRG3 rs10748842 has been associated with illness risk, altered cognitive function, and the expression of a novel splice isoform in prefrontal cortex (PFC), but the neural system effects are unexplored. Here, we report an association between rs10748842 and PFC physiology as measured by functional magnetic resonance imaging of human working memory performance, where a convincing link between increased genetic risk for schizophrenia and increased activation in some PFC areas has been established. In 410 control individuals (195 males, 215 females), we detected a highly significant effect of NRG3 genotype manifesting as an unanticipated increase in ventrolateral PFC activation in nonrisk-associated C allele carriers. An additional analysis including 78 patients with schizophrenia spectrum disorders (64 males, 14 females) and 123 unaffected siblings (53 males, 70 females) revealed a whole-brain significant genotype by group interaction in right dorsolateral PFC (DLPFC), manifesting as a relative activation increase in healthy controls and siblings (C > T/T) and as a hypoactivation in patients (T/T > C). These observed genotype-dependent effects in PFC were not explained by task performance and did not conform to established locales of prefrontal inefficiency linked to genetic risk for schizophrenia. Our data indicate a complex modulation of brain physiology by rs10748842, which does not fit the simple inefficiency model of risk association in DLPFC and suggests that other neurobiological mechanisms are involved. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 22 | Mol. Psychiatry 2014 May 19: 615-24 |
| PMID | 23752247 |
| Title | Genome-wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample. |
| Abstract | Smoking is a major risk factor for several somatic diseases and is also emerging as a causal factor for neuropsychiatric disorders. Genome-wide association (GWA) and candidate gene studies for smoking behavior and nicotine dependence (ND) have disclosed too few predisposing variants to account for the high estimated heritability. Previous large-scale GWA studies have had very limited phenotypic definitions of relevance to smoking-related behavior, which has likely impeded the discovery of genetic effects. We performed GWA analyses on 1114 adult twins ascertained for ever smoking from the population-based Finnish Twin Cohort study. The availability of 17 smoking-related phenotypes allowed us to comprehensively portray the dimensions of smoking behavior, clustered into the domains of smoking initiation, amount smoked and ND. Our results highlight a locus on 16p12.3, with several single-nucleotide polymorphisms (SNPs) in the vicinity of CLEC19A showing association (P<1 × 10(-6)) with smoking quantity. Interestingly, CLEC19A is located close to a previously reported attention-deficit hyperactivity disorder (ADHD) linkage locus and an evident link between ADHD and smoking has been established. Intriguing preliminary association (P<1 × 10(-5)) was detected between DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) ND diagnosis and several SNPs in ERBB4, coding for a Neuregulin receptor, on 2q33. The association between ERBB4 and DSM-IV ND diagnosis was replicated in an independent Australian sample. Recently, a significant increase in ErbB4 and Neuregulin 3 (NRG3) expression was revealed following chronic nicotine exposure and withdrawal in mice and an association between NRG3 SNPs and smoking cessation success was detected in a clinical trial. ERBB4 has previously been associated with schizophrenia; further, it is located within an established schizophrenia linkage locus and within a linkage locus for a smoker phenotype identified in this sample. In conclusion, we disclose novel tentative evidence for the involvement of ERBB4 in ND, suggesting the involvement of the Neuregulin/ErbB signalling pathway in addictions and providing a plausible link between the high co-morbidity of schizophrenia and ND. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 23 | Ann Gen Psychiatry 2014 -1 13: 18 |
| PMID | 24976857 |
| Title | Cognitive outcome and gamma noise power unrelated to neuregulin 1 and 3 variation in schizophrenia. |
| Abstract | Neuregulins are a family of signalling proteins that orchestrate a broad range of cellular responses. Four genes encoding Neuregulins 1-4 have been identified so far in vertebrates. Among them, Neuregulin 1 and Neuregulin 3 have been reported to contribute to an increased risk for developing schizophrenia. We hypothesized that three specific variants of these genes (rs6994992 and rs3924999 for Neuregulin 1 and rs10748842 for Neuregulin 3) that have been related to this illness may modify information processing capacity in the cortex, which would be reflected in electrophysiological parameters (P3b amplitude or gamma noise power) and/or cognitive performance. We obtained DNA from 31 patients with schizophrenia and 23 healthy controls and analyzed NRG1 rs6994992, NRG1 rs3924999 and NRG3 rs10748842 promoter polymorphisms by allelic discrimination with real-time polymerase chain reaction (PCR). We compared cognitive outcome, P300 amplitude parameters and an electroencephalographic measure of noise power in the gamma band between the groups dichotomized according to genotype. Contrary to our hypothesis, we could not detect any significant influence of variation in Neuregulin 1/Neuregulin 3 polymorphisms on cognitive performance or electrophysiological parameters of patients with schizophrenia. Despite our findings, we cannot discard that other genetic variants and, more likely, interactions between those variants and with genetic variation related to different pathways may still influence cerebral processing in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 24 | Front Neurosci 2014 -1 8: 389 |
| PMID | 25561905 |
| Title | Impulsivity and comorbid traits: a multi-step approach for finding putative responsible microRNAs in the amygdala. |
| Abstract | Malfunction of synaptic plasticity in different brain regions, including the amygdala plays a role in impulse control deficits that are characteristics of several psychiatric disorders, such as ADHD, schizophrenia, depression and addiction. Previously, we discovered a locus for impulsivity (Impu1) containing the neuregulin 3 (NRG3) gene, of which the level of expression determines levels of inhibitory control. MicroRNAs (miRNAs) are potent regulators of gene expression, and have recently emerged as important factors contributing to the development of psychiatric disorders. However, their role in impulsivity, as well as control of NRG3 expression or malfunction of the amygdala, is not well established. Here, we used the GeneNetwork database of BXD mice to search for correlated traits with impulsivity using an overrepresentation analysis to filter for biologically meaningful traits. We determined that inhibitory control was significantly correlated with expression of miR-190b, -28a, -340, -219a, and -491 in the amygdala, and that the overrepresented correlated traits showed a specific pattern of coregulation with these miRNAs. A bioinformatics analysis identified that miR-190b, by targeting an NRG3-related network, could affect synaptic plasticity in the amygdala, targeting bot impulsive and compulsive traits. Moreover, miR-28a, -340, -219a, and possibly -491 could act on synaptic function by determining the balance between neuronal outgrowth and differentiation. We propose that these miRNAs are attractive candidates of regulation of amygdala synaptic plasticity, possibly during development but also in maintaining the impulsive phenotype. These results can help us to better understand mechanisms of synaptic dysregulation in psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 25 | Int. Rev. Neurobiol. 2015 -1 124: 113-31 |
| PMID | 26472527 |
| Title | Role of the Neuregulin Signaling Pathway in Nicotine Dependence and Co-morbid Disorders. |
| Abstract | Smoking is currently the leading cause of preventable death in the United States and is responsible for over four million deaths annually worldwide. Therefore, there is a vast clinical unmet need with regards to therapeutics targeting smoking cessation. This is even more apparent when examining smokers co-morbid with psychiatric illness, as rates of smoking in this population are ~4× higher than in the general population. Examining common genetic and molecular signaling pathways impinging upon both smoking behavior and psychiatric illness will lead to a better understanding of co-morbid disorders and potential development of novel therapeutics. Studies have implicated the Neuregulin Signaling Pathway in the pathophysiology of a number of psychiatric illnesses. Additionally, recent studies have also shown an association between the Neuregulin Signaling Pathway and smoking behaviors. This review outlines basic mechanisms of the Neuregulin Signaling Pathway and how it may be exploited for precision medicine approaches in treating nicotine dependence and mental illness. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 26 | Meta Gene 2015 Sep 5: 135-9 |
| PMID | 26925374 |
| Title | Secondary association of PDLIM5 with paranoid schizophrenia in Emirati patients. |
| Abstract | schizophrenia is a clinically and genetically heterogeneous disorder of unknown etiology. PDLIM5 variants have been linked to schizophrenia and other related neuropsychiatric disorders and upregulated in the brain of schizophrenia patients suggesting a possible pathogenic role in disease progression. The aim of this study is to examine the potential association of schizophrenia in Emirati patients with previously reported variants in PDLIM5, PICK1, NRG3 or DISC1 genes. Consequently, we found a secondary association between PDLIM5 variants and the paranoid subtype of schizophrenia in Emirati Arabs suggesting that PDLIM5 may represent a determinate/marker for schizophrenia subtype specification. However, no associations were found with variants in PICK1, NRG3 or DISC1 genes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 27 | Int. J. Biochem. Cell Biol. 2015 Apr 61: 53-62 |
| PMID | 25681686 |
| Title | PTPN21 exerts pro-neuronal survival and neuritic elongation via ErbB4/NRG3 signaling. |
| Abstract | Although expression quantitative trait locus, eQTL, serves as an explicit indicator of gene-gene associations, challenges remain to disentangle the mechanisms by which genetic variations alter gene expression. Here we combined eQTL and molecular analyses to identify an association between two seemingly non-associated genes in brain expression data from BXD inbred mice, namely Ptpn21 and NRG3. Using biotinylated receptor tracking and immunoprecipitation analyses, we determined that PTPN21 de-phosphorylates the upstream receptor tyrosine kinase ErbB4 leading to the up-regulation of its downstream signaling. Conversely, kinase-dead ErbB4 (K751R) or phosphatase-dead PTPN21 (C1108S) mutants impede PTPN21-dependent signaling. Furthermore, PTPN21 also induced Elk-1 activation in embryonic cortical neurons and a novel Elk-1 binding motif was identified in a region located 1919bp upstream of the NRG3 initiation codon. This enables PTPN21 to promote NRG3 expression through Elk-1, which provides a biochemical mechanism for the PTPN21-NRG3 association identified by eQTL. Biologically, PTPN21 positively influences cortical neuronal survival and, similar to Elk-1, it also enhances neuritic length. Our combined approaches show for the first time, a link between NRG3 and PTPN21 within a signaling cascade. This may explain why these two seemingly unrelated genes have previously been identified as risk genes for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 28 | Mol Neuropsychiatry 2015 May 1: 36-46 |
| PMID | 26528484 |
| Title | Identification and functional studies of regulatory variants responsible for the association of NRG3 with a delusion phenotype in schizophrenia. |
| Abstract | We previously reported genetic linkage for schizophrenia (SZ) (NPL of 4.7) at 10q22 in the Ashkenazi Jewish (AJ) population. In follow up fine mapping we found strong evidence of association between three intronic single nucleotide variants (SNVs) in the 5' end of Neuregulin 3 (NRG3) and the delusion factor score of our phenotypic principal component analysis. Two independent groups replicated these findings, indicating that variants in NRG3 confer risk for a delusion-rich SZ subtype. To identify the causative variants, we sequenced the 162 kb linkage disequilibrium (LD) block covering the NRG3 5' end in 47 AJ SZ patients at the extremes of the delusion factor quantitative trait distribution. Among the identified variants we found 5 noncoding SNVs present on the high delusion factor haplotype and significantly overrepresented in high delusion factor subjects. We tested these for regulatory effects and found that risk alleles of rs10883866 and rs60827755 decreased and increased, respectively, the expression of a reporter gene as compared to the reference allele. In post-mortem brain RNA quantification experiments we found the same variants also perturb relative expression of alternative NRG3 isoforms. In summary, we have identified regulatory SNVs contributing to the association of NRG3 with delusion symptoms in SZ. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 29 | J. Neurochem. 2016 Jan 136: 234-49 |
| PMID | 26465092 |
| Title | Neurological dysfunctions associated with altered BACE1-dependent Neuregulin-1 signaling. |
| Abstract | Inhibition of BACE1 is being pursued as a therapeutic target to treat patients suffering from Alzheimer's disease because BACE1 is the sole ?-secretase that generates ?-amyloid peptide. Knowledge regarding other cellular functions of BACE1 is therefore critical for the safe use of BACE1 inhibitors in human patients. Neuregulin-1 (Nrg1) is a BACE1 substrate and BACE1 cleavage of Nrg1 is critical for signaling functions in myelination, remyelination, synaptic plasticity, normal psychiatric behaviors, and maintenance of muscle spindles. This review summarizes the most recent discoveries associated with BACE1-dependent Nrg1 signaling in these areas. This body of knowledge will help to provide guidance for preventing unwanted Nrg1-based side effects following BACE1 inhibition in humans. To initiate its signaling cascade, membrane anchored Neuregulin (Nrg), mainly type I and III ?1 Nrg1 isoforms and NRG3, requires ectodomain shedding. BACE1 is one of such indispensable sheddases to release the functional Nrg signaling fragment. The dependence of Nrg on the cleavage by BACE1 is best manifested by disrupting the critical role of Nrg in the control of axonal myelination, schizophrenic behaviors as well as the formation and maintenance of muscle spindles. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 30 | J. Neurochem. 2016 Jan 136: 234-49 |
| PMID | 26465092 |
| Title | Neurological dysfunctions associated with altered BACE1-dependent Neuregulin-1 signaling. |
| Abstract | Inhibition of BACE1 is being pursued as a therapeutic target to treat patients suffering from Alzheimer's disease because BACE1 is the sole ?-secretase that generates ?-amyloid peptide. Knowledge regarding other cellular functions of BACE1 is therefore critical for the safe use of BACE1 inhibitors in human patients. Neuregulin-1 (Nrg1) is a BACE1 substrate and BACE1 cleavage of Nrg1 is critical for signaling functions in myelination, remyelination, synaptic plasticity, normal psychiatric behaviors, and maintenance of muscle spindles. This review summarizes the most recent discoveries associated with BACE1-dependent Nrg1 signaling in these areas. This body of knowledge will help to provide guidance for preventing unwanted Nrg1-based side effects following BACE1 inhibition in humans. To initiate its signaling cascade, membrane anchored Neuregulin (Nrg), mainly type I and III ?1 Nrg1 isoforms and NRG3, requires ectodomain shedding. BACE1 is one of such indispensable sheddases to release the functional Nrg signaling fragment. The dependence of Nrg on the cleavage by BACE1 is best manifested by disrupting the critical role of Nrg in the control of axonal myelination, schizophrenic behaviors as well as the formation and maintenance of muscle spindles. |
| SCZ Keywords | schizophrenia, schizophrenic |