Operation of the Schizophrenia Susceptibility Gene, Neuregulin 1, Across Traditional Diagnostic Boundaries to Increase Risk for Bipolar Disorder

University of Birmingham, Birmingham, England, United Kingdom
Archives of General Psychiatry (Impact Factor: 14.48). 07/2005; 62(6):642-8. DOI: 10.1001/archpsyc.62.6.642
Source: PubMed


Family and twin data suggest that, in addition to susceptibility genes specific for bipolar disorder or schizophrenia, genes exist that contribute to susceptibility across the traditional kraepelinian divide. Several studies have provided evidence that variation at the neuregulin 1 (NRG1) gene on chromosome 8p12 influences susceptibility to schizophrenia. The most consistent finding has been that one particular haplotype (the "core" haplotype) is overrepresented in cases compared with control subjects.
To investigate the possible role of NRG1 in bipolar disorder.
Genetic case-control association analysis.
Subjects were unrelated and ascertained from general psychiatric inpatient and outpatient services.
Five hundred twenty-nine patients with DSM-IV bipolar I disorder and 1011 controls from the United Kingdom (100% white).
We genotyped the markers constituting the NRG1 core haplotype in cases and controls and reanalyzed our existing data from 573 DSM-IV schizophrenia cases with this larger set of controls.
We found a significant difference in haplotype distribution between bipolar cases and controls globally (P = .003) and specifically for the core haplotype. Frequencies were 10.2% for bipolar cases and 7.8% for controls (effect size, as measured by odds ratio [OR], 1.37; 95% confidence interval [CI], 1.03-1.80; P = .04). The effect size in our bipolar sample was similar to that in our schizophrenia sample (OR, 1.22; 95% CI, 0.92-1.61). In the bipolar cases with predominantly mood-incongruent psychotic features (n = 193), the effect was greater (OR, 1.71; 95% CI, 1.29-2.59; P = .009), as was the case in the subset of schizophrenia cases (n = 27) who had experienced mania (OR, 1.64; 95% CI, 0.54-5.01).
Our findings suggest that neuregulin 1 plays a role in influencing susceptibility to bipolar disorder and schizophrenia and that it may exert a specific effect in the subset of functional psychosis that has manic and mood-incongruent psychotic features.

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    • "Previous observations indicate that NRG1 may also influence susceptibility to BD and manic psychosis (Green et al., 2005; Thomson et al., 2007). Consistent with that idea, we found that three NRG1 SNPs (rs113317778_E, rs7005606 and rs6468119) confer higher risk to BD than to schizophrenia which suggests that certain psychotic profiles of BD patients show greater association with NRG1 (Green et al., 2005). Importantly, allele A of rs113317778_E is associated with impaired frontal and temporal lobe activations, development of psychotic symptoms , and deficits in cognitive function (Hall et al., 2006). "

    Full-text · Article · Sep 2014 · Schizophrenia Research
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    • "Wen and coworkers have demonstrated that the ErbB4 in parvalbumin interneurons is critical for NRG1 in the regulation of pyramidal neuronal activity and long-term potentiation in adult mouse brain (Wen et al. 2010). Meanwhile, NRG1 is reported to be a bipolar disorder susceptibility gene and an interesting state-dependent biological marker of major depressive disorder (Green et al. 2005; Belzeaux et al. 2010). All these studies suggest that parvalbumin interneurons are major cellular target for NRG1-ErbB4 signaling in the brain, and we therefore hypothesized that the hypofunction of NRG1-ErbB4 signaling in parvalbumin interneurons may be involved in the process of ketamine exerting rapid antidepressant actions in rats subjected to the forced swimming test (FST). "
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    ABSTRACT: Increasing evidence underscores the strong, rapid, and sustained antidepressant properties of ketamine with a good tolerability profile in patients with depression; however, the underlying mechanisms are not fully elucidated. Neuregulin 1 (NRG1) is a bipolar disorder susceptibility gene and a biomarker of major depressive disorder, which regulates pyramidal neuron activity via ErbB4 in parvalbumin interneurons. Moreover, NRG1-ErbB4 signaling is reported to play a key role in the modulation of synaptic plasticity through regulating the neurotransmission. We therefore hypothesized that hypofunction of NRG1-ErbB4 signaling in parvalbumin interneurons is involved in the process of ketamine exerting rapid antidepressant actions in rats subjected to the forced swimming test (FST). The results showed that ketamine reduced the immobility time and latency to feed of rats receiving the FST, downregulated the levels of NRG1, phosphorylated ErbB4 (p-ErbB4), parvalbumin, 67-kDA isoform of glutamic acid decarboxylase (GAD67), gamma-aminobutyric acid (GABA), and upregulated the levels of glutamate in the rat prefrontal cortex and hippocampus. Pretreatment with NRG1 abolished both ketamine's antidepressant effects and ketamine-induced reduction in p-ErbB4, parvalbumin, GAD67, and GABA levels and increase in glutamate levels. These results suggest that the downregulation of NRG1-ErbB4 signaling in parvalbumin interneurons in the rat brain may be a mechanism underlying ketamine's antidepressant properties.
    Full-text · Article · Mar 2014 · Journal of Molecular Neuroscience
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    • "NRG1 interacts with ErbB4 to regulate glutamate signaling via the N-methyl-D-aspartate receptor. The gene was first identified by linkage to chromosome 8p in Icelandic families with schizophrenia,60 followed by association of this gene with BD (single markers: SNP8NRG221533; rs553950, rs327329, rs7007662; haplotypes: NP8NRG221533-rs4298458-SNP8NRG241930-SNP8NRG243177; rs2919390-rs6988339-rs3757930).61,62 However, this was not replicated in an Irish trios study (SNP8NRG221533, 478B14-878, 420M9-139, SNP8NRG243177).63 "
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    ABSTRACT: Bipolar disorder (BD) is a complex disorder with a number of susceptibility genes and environmental risk factors involved in its pathogenesis. In recent years, huge progress has been made in molecular techniques for genetic studies, which have enabled identification of numerous genomic regions and genetic variants implicated in BD across populations. Despite the abundance of genetic findings, the results have often been inconsistent and not replicated for many candidate genes/single nucleotide polymorphisms (SNPs). Therefore, the aim of the review presented here is to summarize the most important data reported so far in candidate gene and genome-wide association studies. Taking into account the abundance of association data, this review focuses on the most extensively studied genes and polymorphisms reported so far for BD to present the most promising genomic regions/SNPs involved in BD. The review of association data reveals evidence for several genes (SLC6A4/5-HTT [serotonin transporter gene], BDNF [brain-derived neurotrophic factor], DAOA [D-amino acid oxidase activator], DTNBP1 [dysbindin], NRG1 [neuregulin 1], DISC1 [disrupted in schizophrenia 1]) to be crucial candidates in BD, whereas numerous genome-wide association studies conducted in BD indicate polymorphisms in two genes (CACNA1C [calcium channel, voltage-dependent, L type, alpha 1C subunit], ANK3 [ankyrin 3]) replicated for association with BD in most of these studies. Nevertheless, further studies focusing on interactions between multiple candidate genes/SNPs, as well as systems biology and pathway analyses are necessary to integrate and improve the way we analyze the currently available association data.
    Full-text · Article · Oct 2013 · Neuropsychiatric Disease and Treatment
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