Support for NRG1 as a Susceptibility Factor for Schizophrenia in a Northern Swedish Isolated Population

Alaerts, Maaike; Ceulemans, Shana; Forero, Diego A.; Moens, Lotte; Zutter, Sonia De; Heyrman, Lien; Lenaerts, An-Sofie; Norrbäck, Karl-Fredrik; Rijk, Peter De; Nilsson, L-G; Goossens, Dirk; Adolfsson, Rolf; Del-Favero, Jurgen

doi:10.1001/archgenpsychiatry.2009.82

Cited by 34 publications

(32 citation statements)

References 59 publications

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“…Notably N-CAMs represent one of the main CSPG cell surface receptor, raising the possibility that abnormalities affecting these two families of molecules may be linked. Gene expression and genetic studies support the idea that neuregulin 1 contributes directly to SZ (Corfas et al, 2004, Hahn et al, 2006, Harrison and Law, 2006, Alaerts et al, 2009). This molecule was found to interact with ECM components and to share many of the CSPG functions (Corfas et al, 2004).…”

Section: Evidence For Ecm Abnormalities In Szmentioning

confidence: 75%

Extracellular matrix abnormalities in schizophrenia

2012

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Emerging evidence points to the involvement of the brain extracellular matrix (ECM) in the pathophysiology of schizophrenia (SZ). Abnormalities affecting several ECM components, including Reelin and chondroitin sulfate proteoglycans (CSPGs), have been described in subjects with this disease. Solid evidence supports the involvement of Reelin, an ECM glycoprotein involved in corticogenesis, synaptic functions and glutamate NMDA receptor regulation, expressed prevalently in distinct populations of GABAergic neurons, which secrete it into the ECM. Marked changes of Reelin expression in SZ have typically been reported in association with GABA-related abnormalities in subjects with SZ and bipolar disorder. Recent findings from our group point to substantial abnormalities affecting CSPGs, a main ECM component, in the amygdala and entorhinal cortex of subjects with schizophrenia, but not bipolar disorder. Striking increases of glial cells expressing CSPGs were accompanied by reductions of perineuronal nets, CSPG- and Reelin-enriched ECM aggregates enveloping distinct neuronal populations. CSPGs developmental and adult functions, including neuronal migration, axon guidance, synaptic and neurotransmission regulation are highly relevant to the pathophysiology of SZ. Together with reports of anomalies affecting several other ECM components, these findings point to the ECM as a key component of the pathology of SZ. We propose that ECM abnormalities may contribute to several aspects of the pathophysiology of this disease, including disrupted connectivity and neuronal migration, synaptic anomalies and altered GABAergic, glutamatergic and dopaminergic neurotransmission.

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Section: Evidence For Ecm Abnormalities In Szmentioning

confidence: 75%

Extracellular matrix abnormalities in schizophrenia

2012

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“…45–52 Many of them involve RELN. Two of the SNPs involve an interaction between RELN and PDE4B alleles.…”

Section: Resultsmentioning

confidence: 99%

Statistical epistasis and progressive brain change in schizophrenia: an approach for examining the relationships between multiple genes

Andreasen

Wilcox

et al. 2011

Mol Psychiatry

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Although schizophrenia is generally considered to occur as a consequence of multiple genes that interact with one another, very few methods have been developed to model epistasis. Phenotype definition has also been a major challenge for research on the genetics of schizophrenia. In this report we use novel statistical techniques to address the high dimensionality of genomic data, and we apply a refinement in phenotype definition by basing it on the occurrence of brain changes during the early course of the illness, as measured by repeated MR scans (i.e., an “intermediate phenotype.” The method combines a machine learning algorithm, the ensemble method using stochastic gradient boosting, with traditional general linear model statistics. We began with fourteen genes that are relevant to schizophrenia based on association studies or their role in neurodevelopment and then used statistical techniques to reduce them to five genes and 17 SNPs that had a significant statistical interaction: 5 for PDE4B, 4 for RELN, 4 for ERBB4, 3 for DISC1, and one for NRG1. Five of the SNPs involved in these interactions replicate previous research, in that these five SNPs have previously been identified as schizophrenia vulnerability markers or implicate cognitive processes relevant to schizophrenia. This ability to replicate previous work suggests that our method has potential for detecting a meaningful epistatic relationships among the genes that influence brain abnormalities in schizophrenia.

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“…CN as an upstream gene for EGR3 might be triggered by calcium influx through NMDARs [42]. EGR3 is also a target gene for Brain-derived neurotrophic factor (BDNF) and Neuregulin 1 (NRG1) [43], [44], [45], both of which are schizophrenia susceptibility genes [6], [46], [47], [48], [49]. Induction of EGR3 by BDNF enables EGR3 to control the expression of Gamma-aminobutyric acid receptor (GABAR) [50], which is also a candidate risk gene for the schizophrenia [51].…”

Section: Discussionmentioning

confidence: 99%

Genetic Evidence for the Association between the Early Growth Response 3 (EGR3) Gene and Schizophrenia

Zhang

et al. 2012

PLoS ONE

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Recently, two genome scan meta-analysis studies have found strong evidence for the association of loci on chromosome 8p with schizophrenia. The early growth response 3 (EGR3) gene located in chromosome 8p21.3 was also found to be involved in the etiology of schizophrenia. However, subsequent studies failed to replicate this finding. To investigate the genetic role of EGR3 in Chinese patients, we genotyped four SNPs (average interval ∼2.3 kb) in the chromosome region of EGR3 in 470 Chinese schizophrenia patients and 480 healthy control subjects. The SNP rs35201266 (located in intron 1 of EGR3) showed significant differences between cases and controls in both genotype frequency distribution (P = 0.016) and allele frequency distribution (P = 0.009). Analysis of the haplotype rs35201266-rs3750192 provided significant evidence for association with schizophrenia (P = 0.0012); a significant difference was found for the common haplotype AG (P = 0.0005). Furthermore, significant associations were also found in several other two-, and three-SNP tests of haplotype analyses. The meta-analysis revealed a statistically significant association between rs35201266 and schizophrenia (P = 0.0001). In summary, our study supports the association of EGR3 with schizophrenia in our Han Chinese sample, and further functional exploration of the EGR3 gene will contribute to the molecular basis for the complex network underlying schizophrenia pathogenesis.

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Support for NRG1 as a Susceptibility Factor for Schizophrenia in a Northern Swedish Isolated Population

Abstract: The NRG1 gene contributes to the susceptibility for schizophrenia in the northern Swedish population.

Cited by 34 publications

References 59 publications

Extracellular matrix abnormalities in schizophrenia

Extracellular matrix abnormalities in schizophrenia

Statistical epistasis and progressive brain change in schizophrenia: an approach for examining the relationships between multiple genes

Genetic Evidence for the Association between the Early Growth Response 3 (EGR3) Gene and Schizophrenia

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