Neuregulin 1: genetic support for schizophrenia subtypes

Bakker, Selma; Hoogendoorn, Mechteld L.C.; Selten, J.P.; Verduijn, Willem; Pearson, P.; Sinke, Richard J.; Kahn, René S.

doi:10.1038/sj.mp.4001564

Cited by 74 publications

(60 citation statements)

References 15 publications

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“…SNP8NRG221533, which gave the single best-uncorrected association in the original report by Stefansson et al, 4 also showed association in our sample (P = 0.04), although we observed overtransmission of the 'T' allele rather than the 'C' allele, as also reported for a Dutch schizophrenia sample. 35 We also found evidence for association between the core haplotype, comprised of SNP8NRG221533, 478B14-848 and 420M9-1395, global P = 0.05. However, the strongest evidence for association in our sample was observed with several novel four-marker haplotypes.…”

Section: Resultssupporting

confidence: 58%

“…Finally, the association with premorbid developmental delays/dysfunction supports a general influence on earlier brain development before the age range for our MRI measurements. The observation of association with the opposite allele to the one initially reported by Stefansson and others for SNP8NRG221533 was disconcerting; however, a recent report from Bakker et al 35 reported overtransmission of the T allele as well. In the schizophrenia genetics literature, differing allele, SNP and haplotype associations across studies are common 39 and complicate the interpretation of these findings.…”

Section: Discussionmentioning

confidence: 71%

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Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

Addington¹,

Gornick²,

Shaw³

et al. 2006

Mol Psychiatry

110

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Childhood-onset schizophrenia (COS), defined as onset of psychosis by the age of 12, is a rare and malignant form of the illness, which may have more salient genetic influence. Since the initial report of association between neuregulin 1 (NRG1) and schizophrenia in 2002, numerous independent replications have been reported. In the current study, we genotyped 56 markers (54 single-nucleotide polymorphisms (SNPs) and two microsatellites) spanning the NRG1 locus on 78 COS patients and their parents. We used family-based association analysis for both diagnostic (extended transmission disequilibrium test) and quantitative phenotypes (quantitative transmission disequilibrium test) and mixed-model regression. Most subjects had prospective anatomic brain magnetic resonance imaging (MRI) scans at 2-year intervals. Further, we genotyped a sample of 165 healthy controls in the MRI study to examine genetic risk effects on normal brain development. Individual markers showed overtransmission of alleles to affecteds (P = 0.009-0.05). Further, several novel four-marker haplotypes demonstrated significant transmission distortion. There was no evidence of epistasis with SNPs in erbB4. The risk allele (0) at 420M9-1395 was associated with poorer premorbid social functioning. Further, possession of the risk allele was associated with different trajectories of change in lobar volumes. In the COS group, risk allele carriers had greater total gray and white matter volume in childhood and a steeper rate of subsequent decline in volume into adolescence. By contrast, in healthy children, possession of the risk allele was associated with different trajectories in gray matter only and was confined to frontotemporal regions, reflecting epistatic or other illness-specific effects mediating NRG1 influence on brain development in COS. This replication further documents the role of NRG1 in the abnormal brain development in schizophrenia. This is the first demonstration of a disease-specific pattern of gene action in schizophrenia.

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Section: Resultssupporting

confidence: 58%

Section: Discussionmentioning

confidence: 71%

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

Addington¹,

Gornick²,

Shaw³

et al. 2006

Mol Psychiatry

110

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“…It is therefore interesting to note that Green et al 24 showed that subgroups of the two disorders, bipolar disorder with predominantly mood-incongruent psychotic features and schizophrenic cases who had experienced mania, showed a stronger association in their sample. Similarly, Bakker et al 48 reported that, while schizophrenia was not associated with the two Hap ICE markers examined, a subgroup of nondeficit schizophrenia was associated, and Kampman et al 49 reported association of the single Hap ICE SNP tested in only schizophrenic individuals who do not respond to conventional antipsychotics (P = 0.013). These results may indicate that subgroups of schizophrenia and bipolar disorder are associated with NRG1, and further that some regions of the gene may confer risk to both bipolar and schizophrenia and others to only one of the diagnoses.…”

Section: Discussionmentioning

confidence: 93%

Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population

et al. 2006

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Neuregulin 1 (NRG1) is a strong candidate for involvement in the aetiology of schizophrenia. A haplotype, initially identified as showing association in the Icelandic and Scottish populations, has shown a consistent effect size in multiple European populations. Additionally, NRG1 has been implicated in susceptibility to bipolar disorder. In this first study to select markers systematically on the basis of linkage disequilibrium across the entire NRG1 gene, we used haplotype-tagging single-nucleotide polymorphisms to identify single markers and haplotypes associated with schizophrenia and bipolar disorder in an independently ascertained Scottish population. Haplotypes in two regions met an experiment-wide significance threshold of P = 0.0016 (Nyholt's SpD) and were permuted to correct for multiple testing. Region A overlaps with the Icelandic haplotype and shows nominal association with schizophrenia (P = 0.00032), bipolar disorder (P = 0.0011), and the combined case group (P = 0.0017). This region includes the 5 0 exon of the NRG1 GGF2 isoform and overlaps the expressed sequence tag (EST) cluster Hs.97362. However, no haplotype in Region A remains significant after permutation analysis (P > 0.05). Region B contains a haplotype associated with both schizophrenia (P = 0.00014), and the combined case group (P = 0.000062), although it does not meet Nyholt's threshold in bipolar disorder alone (P = 0.0022). This haplotype remained significant after permutation analysis in both the schizophrenia and combined case groups (P = 0.024 and P = 0.016, respectively). It spans a B136 kb region that includes the coding sequence of the sensory and motor neuron derived factor (SMDF) isoform and 3 0 exons of all other known NRG1 isoforms. Our study identifies a new of NRG1 region involved in schizophrenia and bipolar disorder in the Scottish population.

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“…The association of SNP8NRG221533 and two other SNPs, rs3924999 and rs2954041, in NRG1 was soon reported in an independent study of Chinese Han schizophrenia family trios (consisting of the father, the mother and the affected offspring) 144 . The genetic association between NRG1 and schizophrenia has been confirmed in follow-up studies in multiple populations in Scotland, Ireland, the United Kingdom, the Netherlands, Korea and China 145,146,147,148,149,150,151,152, 153, 154, 155 . Most of the 80 schizophrenia-associated SNPs are localized to the 5' region 110, 146, 149, 152, 153, 154, 155 and 3' region 149, 150, 152, 155, 156 of NRG1.…”

Section: Nrg1 and Erbb4 As Susceptibility Genesmentioning

confidence: 89%

Neuregulin 1 in neural development, synaptic plasticity and schizophrenia

2008

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Schizophrenia is a highly debilitating mental disorder that affects −1% of the general population, yet it continues to be poorly understood. Recent studies have identified variations in several genes that are associated with this disorder in diverse populations, including those that encode neuregulin 1 (NRG1) and its receptor ErbB4. The past few years have witnessed exciting progress in our knowledge of NRG1 and ErbB4 functions and the biological basis of the increased risk for schizophrenia that is potentially conferred by polymorphisms in the two genes. An improved understanding of the mechanisms by which altered function of NRG1 and ErbB4 contributes to schizophrenia might eventually lead to the development of more effective therapeutics.Schizophrenia is a severe and disabling mental disorder that is characterized by chronic positive symptoms (hallucinations, delusions and thought disorders), negative symptoms (social withdrawal, apathy and emotional blunting) and cognitive deficits. Although schizophrenia is a highly prevalent CNS disorder, it continues to be one of the least understood, primarily owing to its lack of pathological hallmarks. Most, if not all, commonly prescribed antipsychotics are anti-dopaminergic, and their use has been based on the 'classical' dopamine hypothesis, which posits that it is the hyperactivity of dopaminergic transmission that causes positive symptoms 1 . However, current antipsychotics are only modestly effective treatments for the cognitive dysfunction and negative symptoms that are associated with schizophrenia. Moreover, studies on the mechanism of action of antipsychotics have not been particularly informative about the pathogenesis of the disease 2 .Recent genetic studies have provided insight into the possible aetiological mechanisms of this devastating disorder. Schizophrenia has a significant genetic component, and several genes have been associated with the disorder in diverse populations 3 . In particular, the identification of polymorphisms in the genes that encode neuregulin 1 (NRG1) and its receptor ErbB4 has provided a useful starting point from which to better dissect the pathogenic mechanisms of schizophrenia. The past few years have witnessed major progress in our understanding of NRG1 function in neurodevelopment, neurotransmission and synaptic plasticity and of the potential pathological basis of the increased risk that is conferred by polymorphisms in NRG1 and ERBB4. In this Review we briefly discuss the basic signalling machinery of NRG1, review recent findings on the roles of NRG1 and ErbB signalling during development and synaptic plasticity, and explore the implications for the pathophysiology of schizophrenia.Correspondence to: Lin Mei, Email: E-mail: lmei@mcg.edu. NIH Public Access Author ManuscriptNat Rev Neurosci. Author manuscript; available in PMC 2009 May 14. Published in final edited form as:Nat Rev Neurosci. 2008 June ; 9(6): 437-452. doi:10.1038/nrn2392. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript NRG1 an...

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Neuregulin 1: genetic support for schizophrenia subtypes

Cited by 74 publications

References 15 publications

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population

Neuregulin 1 in neural development, synaptic plasticity and schizophrenia

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