Polymorphisms within 5′ end of the Neuregulin 1 gene are genetically associated with schizophrenia in the Chinese population

Tang, Jie; Chen, W Y; He, Guang; Zhou, Jian; Gu, Ning; Feng, Guo; He, Lin

doi:10.1038/sj.mp.4001436

Cited by 101 publications

(60 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These 'at-risk' haplotypes, all shared a common 'core' consisting of five SNPs and two microsatellite markers, the so-called Hap ICE , and extended a length of 290 kb from the 5 0 end of the GGF2 variant of the NRG1 and into the first exon of this splice form (see Figure 1). This finding was replicated in a follow-up study in a Scottish population, 23 and a succession of replication studies in additional populations ensued, including studies in a number of Chinese populations, [24][25][26] an Irish population, 27 a population from the British Isles, 28 and a Portuguese population. 29,30 However, neither these nor the original study have identified the putative disease-causing variant within NRG1.…”

Section: Introductionmentioning

confidence: 75%

“…9,[23][24][25][26][27][28][29]52 Two of the five SNPs defining the at-risk haplotype previously reported 9 were included in this study, SNPnrg2 and SNPnrg4. These two SNPs plus three additional ones typed in this study were located in the area of Hap ICE .…”

Section: Resultsmentioning

confidence: 99%

“…Discrepant findings from the replications studies to date for NRG1 may be a direct result of the distinct allele frequencies and haplotype composition of the gene region for different populations. For example, the Japanese study which could not confirm the association, 31 some of the studies in Chinese populations which found a different haplotype associated, 24,25,52 or the refinement of the associated haplotype as for example in the Irish population. 27 Differences in allele frequencies can even be observed within continental regions and this can be expected to contribute to the failure of replication of an association found in one population and in another population from the same continent in at least some of the cases.…”

Section: Discussionmentioning

confidence: 98%

See 2 more Smart Citations

Extreme population differences across Neuregulin 1 gene, with implications for association studies

et al. 2005

View full text Add to dashboard Cite

Neuregulin 1 (NRG1) is one of the most exciting candidate genes for schizophrenia in recent years since its first association with the disease in an Icelandic population. Since then, many association studies have analysed allele and haplotype frequencies in distinct populations yielding varying results: some have replicated the association, although with different alleles or haplotypes being associated, whereas others have failed to replicate the association. These contradictory results might be attributed to population differences in allele and haplotype frequencies. In order to approach this issue, we have typed 13 SNPs across this large 1.4 Mb gene, including two of the SNPs originally found associated with schizophrenia in the Icelandic population, the objective being to discover if the underlying cause of the association discrepancies to date may be due to population-specific genetic variation. The analyses have been performed in a total of 1088 individuals from 39 populations, covering most of the genetic diversity in the human species. Most of the SNPs analysed displayed differing frequencies according to geographical region. These allele differences are especially relevant in two SNPs located in a large intron of the gene, as shown by the extreme F ST values, which reveal genetic stratification correlated to broad continental areas. This finding may be indicative of the influence of some local selective forces on this gene. Furthermore, haplotype analysis reveals a clear clustering according to geographical areas. In summary, our findings suggest that NRG1 presents extreme population differences in allele and haplotype frequencies. We have given recommendations for taking this into account in future association studies since this diversity could give rise to erroneous results.

show abstract

Section: Introductionmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Extreme population differences across Neuregulin 1 gene, with implications for association studies

et al. 2005

View full text Add to dashboard Cite

show abstract

“…66 Furthermore, different isoforms of NRG1 appear to act as attractants for migrating cortical GABAergic interneurons. 108 These findings are highly intriguing given the reported association between the NRG1 gene and schizophrenia, 33,[52][53][54][55][56][57][58][59] and suggest that defects in GABA A receptor regulation by NRG1 is a possible mechanism by which NRG1 contributes to schizophrenia. Indeed, in a previous study using the same 33 discordant sibpairs as in the present study, we found higher expression of the SMDF isoform of NRG1 in subjects with schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

“…[43][44][45][46][47][48][49] In schizophrenia patient brain samples, markers of GABAergic neurons are reduced in expression and postsynaptic receptor complexes are increased in number. 47,50,51 Furthermore, there is evidence that neuregulin 1 (NRG1) and dysbindin (DTNBP1), two schizophrenia candidate risk genes, 33,[52][53][54][55][56][57][58][59][60][61][62][63][64][65] interact with the GABA A receptor. For example, treatment of the rat hippocampus with NRG1 resulted in lower expression of GABA A receptor subunit transcripts, 66 while dysbindin likely colocalizes with GABA A receptor subunits in the hippocampus, cortex, and cerebellum through its association with beta-dystrobrevin in the dystrophin protein complex.…”

Section: Introductionmentioning

confidence: 99%

Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia

et al. 2005

View full text Add to dashboard Cite

We previously performed a genome-wide linkage scan in Portuguese schizophrenia families that identified a risk locus on chromosome 5q31-q35. This finding was supported by metaanalysis of 20 other schizophrenia genome-wide scans that identified 5q23.2-q34 as the second most compelling susceptibility locus in the genome. In the present report, we took a two-stage candidate gene association approach to investigate a group of gamma-aminobutyric acid (GABA) A receptor subunit genes (GABRA1, GABRA6, GABRB2, GABRG2, and GABRP) within our linkage peak. These genes are plausible candidates based on prior evidence for GABA system involvement in schizophrenia. In the first stage, associations were detected in a Portuguese patient sample with single nucleotide polymorphisms (SNPs) and haplotypes in GABRA1 (P ¼ 0.00062-0.048), GABRP (P ¼ 0.0024-0.042), and GABRA6 (P ¼ 0.0065-0.0088). The GABRA1 and GABRP findings were replicated in the second stage in an independent German family-based sample (P ¼ 0.0015-0.043). Supportive evidence for association was also obtained for a previously reported GABRB2 risk haplotype. Exploratory analyses of the effects of associated GABRA1 haplotypes on transcript levels found altered expression of GABRA6 and coexpressed genes of GABRA1 and GABRB2. Comparison of transcript levels in schizophrenia patients and unaffected siblings found lower patient expression of GABRA6 and coexpressed genes of GABRA1. Interestingly, the GABRA1 coexpressed genes include synaptic and vesicle-associated genes previously found altered in schizophrenia prefrontal cortex. Taken together, these results support the involvement of the chromosome 5q GABA A receptor gene cluster in schizophrenia, and suggest that schizophrenia-associated haplotypes may alter expression of GABA-related genes.

show abstract

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

Alaerts

Ceulemans²,

Forero³

et al. 2009

Arch Gen Psychiatry

View full text Add to dashboard Cite

show abstract

Polymorphisms within 5′ end of the Neuregulin 1 gene are genetically associated with schizophrenia in the Chinese population

Cited by 101 publications

References 7 publications

Extreme population differences across Neuregulin 1 gene, with implications for association studies

Extreme population differences across Neuregulin 1 gene, with implications for association studies

Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia

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

Contact Info

Product

Resources

About