No evidence for linkage in the Irish study of high-density schizophrenia families (ISHDSF)

Department of Psychiatry, Virginia Institute of Psychiatric and Behavioural Genetics, Virginia Commonwealth University, Richmond, VA, USA.
Molecular Psychiatry (Impact Factor: 14.5). 09/2004; 9(8):777-83; image 729. DOI: 10.1038/
Source: PubMed


The neuregulin-1 gene (NRG1) at chromosome 8p21-22 has been implicated as a schizophrenia susceptibility gene in Icelandic, Scottish, Irish and mixed UK populations. The shared ancestry between these populations led us to investigate the NRG1 polymorphisms and appropriate marker haplotypes for linkage and/or association to schizophrenia in the Irish study of high-density schizophrenia families (ISHDSF). Neither single-point nor multi-point linkage analysis of NRG1 markers gave evidence for linkage independent of our pre-existing findings telomeric on 8p. Analysis of linkage disequilibrium (LD) across the 252 kb interval encompassing the 7 marker core Icelandic/Scottish NRG1 haplotype revealed two separate regions of modest LD, comprising markers SNP8NRG255133, SNP8NRG249130 and SNP8NRG243177 (telomeric) and microsatellites 478B14-428, 420M9-1395, D8S1810 and 420M9-116I12 (centromeric). From single marker analysis by TRANSMIT and FBAT we found no evidence for association with schizophrenia for any marker. Haplotype analysis for the three SNPs in LD region 1 and, separately, the four microsatellites in LD region 2 (analyzed in overlapping 2-marker windows), showed no evidence for overtransmission of specific haplotypes to affected individuals. We therefore conclude that if NRG1 does contain susceptibility alleles for schizophrenia, they impact quite weakly on risk in the ISHDSF.

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Available from: Dawn L Thiselton, Aug 08, 2014
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    • "Since this initial report, confirmatory studies of NRG1 association have been reported in different populations in Scotland (Stefansson et al. 2003), China (Li et al. 2004), Hungary (Keri et al. 2009), Japan (Fukui et al. 2006), Sweden (Alaerts et al. 2009), and a second Scottish cohort (Thomson et al. 2007), though the associated haplotype varies between studies. Negative studies of association have also been reported in Japan (Ikeda et al. 2008; Iwata et al. 2004), Ireland (Thiselton et al. 2004), Denmark (Ingason et al. 2006), Spain (Rosa et al. 2007), and the United States (Crowley et al. 2008). "
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    ABSTRACT: A missense polymorphism in the NRG1 gene, Val>Leu in exon 11, was reported to increase the risk of schizophrenia in selected families from the Central Valley region of Costa Rica (CVCR). The present study investigated the relationship between three NRG1 genetic variants, rs6994992, rs3924999, and Val>Leu missense polymorphism in exon 11, in cases and selected controls from an isolated population from the CVCR. Isolated populations can have less genetic heterogeneity and increase power to detect risk variants in candidate genes. Subjects with bipolar disorder (BD, n=358), schizophrenia (SZ, n=273), or unrelated controls (CO, n=479) were genotyped for three NRG1 variants. The NRG1 promoter polymorphism (rs6994992) was related to altered expression of NRG1 Type IV in other studies. The expression of NRG1 type IV in the dorsolateral prefrontal cortex (DLPFC) and the effect of the rs6994992 genotype on expression were explored in a postmortem cohort of BD, SZ, major depressive disorder (MDD) cases, and controls. The missense polymorphism Val>Leu in exon 11 was not significantly associated with schizophrenia as previously reported in a family sample from this population, the minor allele frequency is 4%, thus our sample size is not large enough to detect an association. We observed however an association of rs6994992 with NRG1 type IV expression in DLPFC and a significantly decreased expression in MDD compared to controls. The present results while negative do not rule out a genetic association of these SNPs with BD and SZ in CVCR, perhaps due to small risk effects that we were unable to detect and potential intergenic epistasis. The previous genetic relationship between expression of a putative brain-specific isoform of NRG1 type IV and SNP variation was replicated in postmortem samples in our preliminary study.
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    • "The Icelandic finding of association of Hap ICE with schizophrenia was replicated first in a Scottish population [Stefansson et al., 2003] and later in a European sample (UK/ Irish) [Williams et al., 2003]. Other Caucasian studies, however, have not replicated these findings or have found positive associations corresponding to markers or alleles other than those previously reported [Bakker et al., 2004; Corvin et al., 2004; Kampman et al., 2004; Thiselton et al., 2004; Duan et al., 2005; Ingason et al., 2006]. Associations between the Hap ICE have also been reported in four Chinese samples [Yang et al., 2003; Li et al., 2004] two of which appear to identify the same haplotype in the same region [Tang et al., 2004; Zhao et al., 2004]. "
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    ABSTRACT: Neuregulin 1 (NRG1) is one of the most exciting candidate genes for schizophrenia since its first association with the disorder in an Icelandic population. Since then, many studies have analyzed allele and haplotype frequencies in European and Asian populations in cases and controls yielding varying results. We investigated the association of NRG1 with psychosis in a total sample set of 575 individuals from 151 Spanish nuclear families. We tested eight SNPs across 1.2 Mb along NRG1 including regions previously associated to schizophrenia in association studies. After correction for multiple testing, the TDT analysis for each marker did not show a significant over-transmission of alleles from the parents to the affected offspring for any of the markers (P > 0.05). The haplotypic analysis with TRANSMIT and PDT did not show preferential transmission for any of the haplotypes analyzed in our sample. These results do not seem to suggest that the investigated NRG1 markers play a role in schizophrenia in the Spanish population, although the finding of a trend for association with one SNP in the 3'of the gene warrants further investigation.
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    • "Chromosome 8p has been suggested repeatedly as a linkage region for both SZ and BPD ; however the underlying genes responsible for the linkage signal remain elusive . NRG1 was identified as one candidate gene from this region and was associated with SZ ( Stefansson et al , 2002 ; Stefansson et al , 2003 ; Williams et al , 2003 ; Yang et al , 2003 ; Corvin et al , 2004 ; Li et al , 2004 ; Tang et al , 2004 ; Petryshen et al , 2005 ) and BPD ( Green et al , 2005 ) in some studies but could not be confirmed by others ( Bakker et al , 2004 ; Hong et al , 2004 ; Iwata et al , 2004 ; Thiselton et al , 2004 ; Duan et al , 2005 ; Liu et al , 2005 ) . This inconsistency might be due to several factors including clinical heterogeneity , population stratification , different haplotype structure between populations and limited statistical power . "
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