Support for involvement of neuregulin 1 in schizophrenia pathophysiology

Petryshen, Tracey L.; Middleton, Frank A.; Kirby, Andrew; Aldinger, Kimberly A.; Purcell, Seth; Tahl, A R; Morley, Christopher P.; McGann, L; Gentile, Karen L.; Rockwell, Graham N.; Medeiros, Helena; Carvalho, Célia Barreto; Macedo, António; Dourado, Ana; Valente, J.; Ferreira, C P; Patterson, Nick; Azevedo, M.H.; Daly, Mark J.; Pato, Carlos N.; Pato, Michelle; Sklar, Pamela

doi:10.1038/sj.mp.4001661

Cited by 45 publications

(72 citation statements)

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“…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%

“…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. This implies that either the disease-causing variant is carried on the susceptibility haplotype or that it is in linkage disequilibrium (LD) with it.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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“…59 Briefly, the sample consisted of primary leukocyte cell preparations from 33 age-and gender-matched sibling pairs (22 female, 11 male pairs; 32 schizophrenia and one SA-D discordant pairs) selected from our linkage pedigrees. 32 Of the 33 sibpairs, 32 sibpairs were also genotyped for the same set of markers as the association sample.…”

Section: Subjectsmentioning

confidence: 99%

“…A combined standard normal Z-score was calculated, where the sum of the deviations from expected frequencies (under the null hypothesis of no association) of each sample was divided by the sum of the variances of each sample, as previously described. 59,85 Nominal significance levels were obtained from the Z distribution. This approach provided SNP allele-or haplotype-specific nominal significance levels.…”

Section: Genotypingmentioning

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%

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

et al. 2005

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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.

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Gene expression analysis of peripheral blood leukocytes from discordant sib-pairs with schizophrenia and bipolar disorder reveals points of convergence between genetic and functional genomic approaches

et al. 2005

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We performed global RNA transcript analysis and comprehensive gene group analysis of peripheral blood leukocyte (PBL) RNA from two groups of matched sib-pairs that were discordant for either schizophrenia (n = 33 sib-pairs) or bipolar disorder (n = 5 sib-pairs). The pairs chosen for these analyses were selected from families with known patterns of genetic linkage (5q for schizophrenia and 6q for bipolar disorder). At the single gene level, we obtained lists of the transcripts with the most significant changes in expression and from these lists determined those with the highest degree of predictive power for classifying subjects according to diagnosis in these samples. At the gene group level, we comprehensively analyzed pairwise expression changes of more than 4,000 functional groups and cytogenetic locations, and present a novel method of displaying these data that we term "cytogenomic" mapping. Verification of selected changes in expression was performed using quantitative real-time RT-PCR. Our results provide compelling evidence for the utility of analyzing PBL RNA for changes in expression in neuropsychiatric disorders.

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Support for involvement of neuregulin 1 in schizophrenia pathophysiology

Cited by 45 publications

References 0 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

Gene expression analysis of peripheral blood leukocytes from discordant sib-pairs with schizophrenia and bipolar disorder reveals points of convergence between genetic and functional genomic approaches

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