| 1 | 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 |
| 2 | J. Neurochem. 2008 Mar 104: 1450-65 |
| PMID | 18028338 |
| Title | Cholecystokinin-2 receptor mediated gene expression in neuronal PC12 cells. |
| Abstract | Cholecystokinin (CCK) is abundantly expressed in the CNS, in which it regulates feeding behavior and long-term memory. Moreover, CCK has been implicated in mental disorders, such as anxiety and schizophrenia. Despite its manifest physiological and pathophysiological role, the molecular targets of neuronal CCK are incompletely understood. To identify genes regulated by neuronal CCK, we generated neuronal PC12 cells stably expressing the CCK-2 receptor (CCK-2R) and treated the cells with sulphated CCK-8 for 2-16 h, before the global expression profile was examined. The changes in gene expression peaked after 2 h, with 67 differentially expressed transcripts identified. A pathway analysis indicated that CCK was implicated in the regulation of the circadian clock system, the plasminogen system and cholesterol metabolism. But transcripts encoding proteins involved in dopamine signaling, ornithine decarboxylase (ODC) regulation, memory and epidermal growth factor receptor (EGFR) signaling were also found. Several target genes contained cAMP response elements (CREs), serum response elements (SREs), activator protein 1 (AP1) elements and GC-rich regions, but otherwise no common regulatory promoter element could be identified. Comparison with forskolin- and nerve growth factor (NGF)-treated PC12 cells showed that CCK induced a separate set of target genes. Taken together, we propose that neuronal CCK may have a role in the regulation of the circadian rhythm, the metabolism of cerebral cholesterol and in the regulation of the plasminogen system. |
| SCZ Keywords | schizophrenia |
| 3 | Schizophr Bull 2009 Nov 35: 1163-82 |
| PMID | 18552348 |
| Title | Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii. |
| Abstract | Many genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate endosomal to lysosomal routing that is also important in viral traffic. Neuregulin 1 activates ERBB receptors releasing a factor, EBP1, known to inhibit the influenza virus transcriptase. Other viral or bacterial components bind to genes or proteins encoded by CALR, FEZ1, FYN, HSPA1B, IL2, HTR2A, KPNA3, MED12, MED15, MICB, NQO2, PAX6, PIK3C3, RANBP5, or TP53, while the cerebral infectivity of the herpes simplex virus is modified by Apolipoprotein E (APOE). Genes encoding for proteins related to the innate immune response, including cytokine related (CCR5, CSF2RA, CSF2RB, IL1B, IL1RN, IL2, IL3, IL3RA, IL4, IL10, IL10RA, IL18RAP, lymphotoxin-alpha, tumor necrosis factor alpha [TNF]), human leukocyte antigen (HLA) antigens (HLA-A10, HLA-B, HLA-DRB1), and genes involved in antigen processing (angiotensin-converting enzyme and tripeptidyl peptidase 2) are all concerned with defense against invading pathogens. Human microRNAs (Hsa-mir-198 and Hsa-mir-206) are predicted to bind to influenza, rubella, or poliovirus genes. Certain genes associated with schizophrenia, including those also concerned with neurophysiology, are intimately related to the life cycles of the pathogens implicated in the disease. Several genes may affect pathogen virulence, while the pathogens in turn may affect genes and processes relevant to the neurophysiology of schizophrenia. For such genes, the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen, which varies in different populations at different times, a factor that may explain the heterogeneity that plagues such studies. This scenario also suggests that drugs or vaccines designed to eliminate the pathogens that so clearly interact with schizophrenia susceptibility genes could have a dramatic effect on the incidence of the disease. |
| SCZ Keywords | schizophrenia |
| 4 | Bull. Math. Biol. 2012 Mar 74: 717-35 |
| PMID | 22147103 |
| Title | A model of neuregulin control of NMDA receptors on synaptic spines. |
| Abstract | Neuregulin (Nrg) through its receptor ErbB4 modulates the activity of the N-Methyl-D-Aspartate (NMDA) receptor (NMDAR) at synapses. As modification of this pathway has been implicated in schizophrenia, it is of great interest to define it in precise quantitative terms. Kinetic models of the epidermal growth factor (EGF)/ErbB receptor signalling pathway describing activation, desensitization, and tyrosine phosphorylation of EGFR/ErbB followed by binding and activation of Src family kinases that is subsequently followed by phosphorylation of target proteins are available. We have adapted these to give a kinetic description of NMDAR modulation by Nrg that recapitulates the observed kinetics of autophosphorylation of the ErbB dimer as well as the modulation of the NMDAR by Src kinase, according to whether the kinases are activated or deactivated. This quantitative description of the Nrg/NMDAR pathway provides a model for experimental elucidation of what goes awry in animal models of schizophrenia. |
| SCZ Keywords | schizophrenia |
| 5 | BMC Neurosci 2014 -1 15: 30 |
| PMID | 24552586 |
| Title | Quetiapine and aripiprazole signal differently to ERK, p90RSK and c-Fos in mouse frontal cortex and striatum: role of the EGF receptor. |
| Abstract | Signaling pathways outside dopamine D2 receptor antagonism may govern the variable clinical profile of antipsychotic drugs (APD) in schizophrenia. One postulated mechanism causal to APD action may regulate synaptic plasticity and neuronal connectivity via the extracellular signal-regulated kinase (ERK) cascade that links G-protein coupled receptors (GPCR) and ErbB growth factor signaling, systems disturbed in schizophrenia. This was based upon our finding that the low D2 receptor affinity APD clozapine induced initial down-regulation and delayed epidermal growth factor receptor (EGFR or ErbB1) mediated activation of the cortical and striatal ERK response in vivo distinct from olanzapine or haloperidol. Here we map whether the second generation atypical APDs aripiprazole and quetiapine affect the EGFR-ERK pathway and its substrates p90RSK and c-Fos in mouse brain, given their divergent agonist and antagonist properties on dopaminergic transmission, respectively. In prefrontal cortex, aripiprazole triggered triphasic ERK phosphorylation that was EGFR-independent but had no significant effect in striatum. Conversely quetiapine did not alter cortical ERK signaling but elevated striatal ERK levels in an EGFR-dependent manner. Induction of ERK by aripiprazole did not affect p90RSK signaling but quetiapine decreased RSK phosphorylation within 1-hour of administration. The transcription factor c-Fos by comparison was a direct target of ERK phosphorylation induced by aripiprazole in cortex and quetiapine in striatum with protein levels in temporal alignment with that of ERK. These data indicate that aripiprazole and quetiapine signal to specific nuclear targets of ERK, which for quetiapine occurs via an EGFR-linked mechanism, possibly indicating involvement of this system in its action. |
| SCZ Keywords | schizophrenia |
| 6 | Psychiatry Res 2015 Dec 230: 964-7 |
| PMID | 26596365 |
| Title | Association of age-of-onset groups with GWAS significant schizophrenia and bipolar disorder loci in Romanian bipolar I patients. |
| Abstract | We investigated the influence of the age-of-onset (AO) on the association of 45 loci conferring risk for bipolar disorder (BP) and schizophrenia with BP-type-I in a Romanian sample (461 patients, 436 controls). The AO-analysis implicated the EGFR gene, as well as loci in other genes, in the AO variation of BP-type-I and revealed for the first time the link between BP-type-I and risk variants considered specific to schizophrenia (polymorphisms in MMP16/RIPK2 and CNNM2 genes). |
| SCZ Keywords | schizophrenia |
| 7 | Lancet Psychiatry 2015 Dec 2: 1075-83 |
| PMID | 26453408 |
| Title | Long-term effect of lithium maintenance therapy on estimated glomerular filtration rate in patients with affective disorders: a population-based cohort study. |
| Abstract | For more than 40 years, the long-term effect of lithium maintenance therapy on renal function has been debated. We aimed to assess the effect of lithium maintenance therapy on estimated glomerular filtration rate (eFGR) in patients with affective disorders, and explore predictors for a decrease in EGFR. This population-based cohort study included adult patients (18-65 years of age at baseline) in Tayside (Scotland, UK) who had recently started on lithium maintenance treatment between Jan 1, 2000, and Dec 31, 2011 (retrospectively assigned to the lithium group) or those with exposure to other first-line drugs used in the treatment of affective disorders (quetiapine, olanzapine, and semisodium valproate) during the same period (retrospectively assigned to the comparator group). Patients had to have at least 6 months of (incidence) exposure to lithium or any of the comparator drugs, at least two EGFR values available in the observation period (one at baseline and at least one after ?6 months post baseline). We excluded patients with previous exposure to lithium or one of the comparator drugs, those with a previous diagnosis of schizophrenia or other psychotic disorder, those with glomerular disease, tubulo-interstitial disease, or chronic kidney disease stages 4-5 at baseline, and those who had undergone renal transplant before exposure. Maximum follow-up was 12 years. Data were provided by the University of Dundee Health Informatics Centre, who have access to health-related population-based datasets containing data for every patient registered with a regional family doctor. Each patient has a unique ten-digit identifier, the Community Health Index, enabling us to link laboratory tests, dispensed community prescriptions, Scottish Morbidity Records, and mortality records to the patient. All data were anonymised according to Health Informatics Centre standard operating procedures. The primary outcome was the change per year in the EGFR, adjusted for age, sex, and baseline EGFR, and analysed by random coefficient models. 1120 patients (305 exposed to lithium and 815 to comparator drugs) qualified for inclusion, providing 13?963 EGFR values over 12 years. The mean duration of exposure to lithium was 55 months (SD 42; range 6-144). Mean annual decline in EGFR (adjusted for age, sex, and baseline EGFR) was 1·3 mL/min per 1·73 m(2) (SE 0·2) in the lithium group, which did not differ significantly to that in the comparator group (0·9 mL/min/1·73 m(2) [SE 0·15]). After adjustment for additional confounders, the monthly decline in EGFR attributable to lithium exposure amounted to 0·02 mL/min per 1·73 m(2) (SE 0·02, p=0·30). As a post-hoc secondary outcome, we estimated the annual decline in EGFR for the lithium group to be 1·0 mL/min per 1·73 m(2) (SE 0·2), which again did not differ significantly to that in the comparator group (0·4 mL/min/1·73 m(2) [SE 0·2]. Modelling identified significant predictors for EGFR decline as age, baseline EGFR, comorbidities, co-prescriptions of nephrotoxic drugs, and episodes of lithium toxicity; however, duration of exposure to lithium and mean serum lithium level were not significant predictors for EGFR decline. Our analysis suggests no effect of stable lithium maintenance therapy (lithium levels in therapeutic range) on the rate of change in EGFR over time. Our results therefore contradict the idea that long-term lithium therapy is associated with nephrotoxicity in the absence of episodes of acute intoxication and that duration of therapy and cumulative dose are the major determinants of toxicity. None. |
| SCZ Keywords | schizophrenia |
| 8 | Psychiatry Res 2016 Jun 240: 260-4 |
| PMID | 27138815 |
| Title | Striatal but not frontal cortical up-regulation of the epidermal growth factor receptor in rats exposed to immune activation in utero and cannabinoid treatment in adolescence. |
| Abstract | In utero maternal immune activation (MIA) and cannabinoid exposure during adolescence constitute environmental risk factors for schizophrenia. We investigated these risk factors alone and in combination ("two-hit") on epidermal growth factor receptor (EGFR) and neuregulin-1 receptor (ErbB4) levels in the rat brain. EGFR but not ErbB4 receptor protein levels were significantly increased in the nucleus accumbens and striatum of "two-hit" rats only, with no changes seen at the mRNA level. These findings support region specific EGF-system dysregulation as a plausible mechanism in this animal model of schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia |