Association analysis of Neuregulin 1 candidate regions in schizophrenia and bipolar disorder

Medical Genetics Section, Centre for Molecular Medicine and Institute of Genetics and Molecular Medicine, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
Neuroscience Letters (Impact Factor: 2.03). 06/2010; 478(1):9-13. DOI: 10.1016/j.neulet.2010.04.056
Source: PubMed


Schizophrenia (SCZ) and bipolar disorder (BPD) are severe heritable psychiatric disorders involving a complex genetic aetiology. Neuregulin 1 (NRG1) is a leading candidate gene for SCZ, and has recently been implicated in BPD. We previously reported association of two NRG1 haplotypes with SCZ and BPD in a Scottish case-control sample. One haplotype is located at the 5' end of the gene (region A), and the other is located at the 3' end (region B). Here, association to haplotypes within regions A and B was assessed in patients with SCZ and BPD in a second Scottish case-control sample and in the two Scottish samples combined. Association to region B was also assessed in patients with SCZ and BPD in a German case-control sample, and in all three samples combined. No evidence was found for association in the new samples when analysed individually; however, in the joint analysis of the two Scottish samples, a region B haplotype comprising two SNPs (rs6988339 and rs3757930) was associated with SCZ and the combined case group (SCZ: p=0.0037, OR=1.3, 95% CI: 1.1-1.6; BPD+SCZ: p=0.0080, OR=1.2, 95% CI: 1.1-1.5), with these associations withstanding multiple testing correction at the single-test level (SCZ: p(st)=0.022; BPD+SCZ: p(st)=0.044). This study supports the involvement of NRG1 variants in the less well studied 3' region in conferring susceptibility to SCZ and BPD in the Scottish population.

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    • "A number of genetic loci were consistently found to be associated with schizophrenia. Genes of the major histocompatibility complex (MHC) region on chromosome 6p21.3–22.1 (de Jong et al., 2012; Li et al., 2010; Shi et al., 2009; Stefansson et al., 2009; Wright et al., 1996), the zinc finger protein gene ZNF804A on chromosome 2q32.1 (Hill and Bray, 2012; Kuswanto et al., 2012; Ripke et al., 2011; Williams et al., 2011; Zhang et al., 2011), neuregulin1 (NRG1) on chromosome 8 (Agim et al., 2013; Li et al., 2006; Stefansson et al., 2009; Walker et al., 2010), and transcription factor 4 (TCF4) on chromosome 18q21.2 (Blake et al., 2010; Li et al., 2010; Navarrete et al., 2013; Stefansson et al., 2009) were consistently found to be associated with schizophrenia. "
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    ABSTRACT: schizophrenia is a complex mental disorder marked by severely impaired thinking, delusional thoughts, hallucinations and poor emotional responsiveness. The biological mechanisms that lead to schizophrenia may be related to the genetic background of patients. Thus, a genetic perspective may help to unravel the molecular pathways disrupted in schizophrenia. In the present work, we used a molecular pathway analysis to identify the molecular pathways associated with schizophrenia. We collected data of genetic loci previously associated with schizophrenia, identified the genes located in those positions and created the metabolic pathways that are related to those genes' products. These pathways were tested for enrichment (a number of SNPs associated with the phenotype significantly higher than expected by chance) in a sample of schizophrenic patients and controls (4,486 and 4,477, respectively). The molecular pathway that resulted from the identification of all the genes located in loci previously found to be associated with schizophrenia was found to enriched, as expected (permutated p(10(6))=9.9999e-06).We found 60 SNPs amongst 30 different genes with a strong association with schizophrenia. The genes are related to the pathways related to neurodevelopment, apoptosis, vesicle traffic, immune response and MAPk cascade. The pathway related to the toll-like receptor family seemed to play a central role in the modulation/connection of various pathways whose disruption leads to schizophrenia. This pathway is related to the innate immune system, further stressing the role of immunological-related events in increasing the risk to schizophrenia. Copyright © 2014. Published by Elsevier Inc.
    Full-text · Article · Dec 2014 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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    • "Accumulating evidence from human genetic studies suggests that multiple susceptibility genes or loci, including Neuregulin 1 (NRG1) (Schwab and Wildenauer, 2009), might contribute to the pathogenesis of schizophrenia. The association between NRG1 and schizophrenia was initially revealed in a study of families in Iceland (Stefansson et al., 2002), and the association has been further confirmed in other ethnic groups (Walker et al., 2010). Reduced levels of the expression of NRG1 have also been reported in schizophrenic post-mortem tissues (Bertram et al., 2007; Nicodemus et al., 2009; Parlapani et al., 2010), which indicates that alterations in NRG1 might contribute to the pathophysiology of schizophrenia. "
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    ABSTRACT: Accumulating evidence suggests that neuregulin 1 (NRG1) might be involved in the neurodevelopment, neural plasticity, GABAergic neurotransmission, and pathogenesis of schizophrenia. NRG1 is abundantly expressed in the hippocampus, and emerging studies have begun to reveal the link between NRG1 signaling and cognitive deficits in schizophrenic patients. Because the transmembrane domain of NRG1 is vital for both forward and reverse signaling cascades, new Nrg1-deficient mice that carry a truncation of the transmembrane domain of the Nrg1 gene were characterized and used in this study to test a NRG1 loss-of-function hypothesis for schizophrenia. Both male and female Nrg1 heterozygous mutant mice and their wild-type littermates were used in a series of 4 experiments to characterize the impact of Nrg1 on behavioral phenotypes and to determine the importance of Nrg1 in the regulation of hippocampal neuromorphology and local GABAergic interneurons. First, a comprehensive battery of behavioral tasks indicated that male Nrg1-deficient mice exhibited significant impairments in cognitive functions. Second, pharmacological challenges were conducted and revealed that Nrg1 haploinsufficiency altered GABAergic activity in males. Third, although no genotype-specific neuromorphological alterations were found in the hippocampal CA1 pyramidal neurons, significant reductions in the hippocampal expressions of GAD67 and parvalbumin were revealed in the Nrg1-deficient males. Fourth, chronic treatment with valproate rescued the observed behavioral deficits and hippocampal GAD67 reduction in Nrg1-deficient males. Collectively, these results indicate the potential therapeutic effect of valproate and the importance of Nrg1 in the regulation of cognitive functions and hippocampal GABAergic interneurons, especially in males.
    Full-text · Article · Apr 2014 · Frontiers in Behavioral Neuroscience
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    • "(DISC1) [e.g., Hodgkinson et al., 2004], neuregulin 1 [e.g., Green et al., 2005; Walss-Bass et al., 2006; Walker et al., 2010], and ZNF804A [e.g., Williams et al., 2011] also show significant association with BPD provide increasing support for the possibility of shared biological pathways across the SCZ–BPD continuum. A recent genome-wide association study (GWAS) of a collaborative European case-control sample found that common polygenic variation contributes to risk for both SCZ and BPD [Purcell et al., 2009]. "
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    ABSTRACT: Growing evidence for genetic overlap between schizophrenia (SCZ) and bipolar disorder (BPD) suggests that causal variants of large effect on disease risk may cross traditional diagnostic boundaries. Extended multigenerational families with both SCZ and BPD cases can be a valuable resource for discovery of shared biological pathways because they can reveal the natural evolution of the underlying genetic disruptions and their phenotypic expression. We investigated a deletion at the SLC1A1 glutamate transporter gene originally identified as a copy number variant exclusively carried by members of a 5-generation Palauan family. Using an expanded sample of 21 family members, quantitative PCR confirmed the deletion in all seven individuals with psychosis, three "obligate-carrier" parents and one unaffected sibling, while four marry-in parents were non-carriers. Linkage analysis under an autosomal dominant model generated a LOD-score of 3.64, confirming co-segregation of the deletion with psychosis. For more precise localization, we determined the approximate deletion end points using alignment of next-generation sequencing data for one affected deletion-carrier and then designed PCR amplicons to span the entire deletion locus. These probes established that the deletion spans 84,298 bp, thus eliminating the entire promoter, the transcription start site, and the first 59 amino acids of the protein, including the first transmembrane Na(2+) /dicarboxylate symporter domain, one of the domains that perform the glutamate transport action. Discovery of this functionally relevant SLC1A1 mutation and its co-segregation with psychosis in an extended multigenerational pedigree provides further support for the important role played by glutamatergic transmission in the pathophysiology of psychotic disorders. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Mar 2013 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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