Confirmation and refinement of an ‘at-risk’ haplotype for schizophrenia suggests the EST cluster, Hs.97362, as a potential susceptibility gene at the Neuregulin-1 locus

Abstract

Two recent association studies have implicated the neuregulin-1 gene (NRG1) at chromosome 8p21-22 as a susceptibility gene for schizophrenia. Stefansson et al identified three 'at-risk' haplotypes (HapA, B and C) which spanned the NRG1 locus and shared a common core haplotype. Subsequently, they demonstrated evidence that the core haplotype was associated with schizophrenia in an independent Scottish sample. To confirm and refine this haplotype we investigated the NRG1 locus in an independent Irish case-control sample. We did not find the core haplotype to be associated in our sample. However, we identified a refined 2-marker haplotype (HapB(IRE)) that shared common alleles with one of the Icelandic 'at-risk' haplotypes and is in significant excess in the Irish cases (19.4%) vs controls (12.3%) (P=0.013). This refined 'at-risk' haplotype is also in significant excess in the Scottish case sample (17.0% vs 13.5%; P=0.036). Interestingly, this refined 'at-risk' haplotype is positioned close to an EST cluster of unknown function (Hs.97362) within intron 1 of NRG1.

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

“…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.…”

“…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 .…”

“…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. In the case of European populations where the greatest number of association studies tend to be carried out, there have been some notable failures to replicate association studies, as mentioned before in the case of schizophrenia the failure of replication in one of the studies of involving an Irish population.…”

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

“…[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.…”

First family-based test for association of neuregulin with bipolar affective disorder

“…Interestingly, this marker was selected based on its presence within an Irish schizophrenia-associated haplotype, HapB IRE . 7 A range of two to three marker haplotypes, including HAP ICE and HapB IRE , also failed to exhibit any evidence of association with BPAD (Table 1). A haplotype comprised of alleles from the three microsatellite markers (M3-M4-M5) did exhibit a marginal association (Table 1, haplotype 1, 3, 5, uncorrected P = 0.04) which was not significant at the global haplotype level (Table 1: P = 0.31).…”