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Functional Neuregulin Variant Linked to Psychosis, Abnormal Brain Activation and IQ

30 October 2006. A high-risk haplotype of the candidate schizophrenia susceptibility gene neuregulin 1 (NRG1), and in particular a single nucleotide polymorphism associated with altered expression, has now been linked with increased psychotic symptoms, abnormal frontal and temporal lobe activation, and lower adult intelligence quotient (IQ) in young adults already at high risk of the disease. The study, by Jeremy Hall and colleagues from the University of Edinburgh, was published online in Nature Neuroscience on October 29.

As a candidate susceptibility gene for schizophrenia, NRG1 is supported by a strong body of evidence (Li et al., 2006). A risk-associated haplotype of NRG1, called the deCODE (or Icelandic) haplotype, has been identified at the 5’ end of the gene (Stefansson et al., 2002) and has been confirmed in the Scottish population (Stefansson et al., 2003). Work published earlier this year by Amanda Law and colleagues from Oxford University, England, and the National Institutes of Health, Bethesda, Maryland, found that the risk allele SNP8NRG243177, which is part of the original deCODE haplotype, is associated with increased expression of the type IV NRG1 transcript in postmortem brain tissue (Law et al., 2006; also see SRF related news story). This effect appears to be due to changes in three transcription factor binding sites in NRG1, those for serum response factor, myelin transcription factor-1, and High Mobility Group Box Protein-1.

In this study, a collaboration between the groups led by Eve Johnstone and David Porteous, Hall and colleagues examined the effects of the SNP8NRG243177 risk allele on the development of psychotic symptoms, brain function, and adult IQ in participants from the Edinburgh High Risk Study (Johnstone et al., 2000). The 79 subjects were aged 16-25, were from families with at least two individuals affected by schizophrenia, and were followed up regularly for up to 10 years. DNA samples were collected from study participants and were genotyped for single nucleotide polymorphisms (SNPs) from the deCODE haplotype (SNP8NRG221132, SNP8NRG221533, SNP8NRG241930, and SNP8NRG243177 and the microsatellites 478B14-848 and 420M9-1395).

The authors found that the SNP8NRG243177 genotype was strongly associated with the development of psychotic symptoms in this sample (Fisher’s exact test 13.5, P = 0.001), and the effect remained significant when related subjects were removed from the analysis. Although each of the other markers was analyzed, no association with the development of psychotic symptoms was found. When all four SNPs of the deCODE haplotype were analyzed together, an association with psychotic symptoms was found, albeit at a lower level of significance than that seen with SNP8NRG243177 alone (Fisher’s exact test 8.4, P <0.05).

Hall and colleagues next conducted an analysis of brain activation in their cohort using functional magnetic resonance imaging (fMRI). Participants performed the Hayling sentence completion task, known to activate frontal and temporal brain regions, while undergoing fMRI. A failure to properly integrate these brain regions has been theorized to underlie psychosis (Friston and Frith, 1995). The authors found that subjects with the risk genotype showed significantly less activation of medial prefrontal cortex (Brodmann area 9) and right temporo-occipital junction (Brodmann areas 39 and 19) than did those without this genotype; the effect was still significant after the removal of related individuals from the groups. In addition, no differences in grey matter density were found between groups in these brain regions by voxel-based morphometry.

Lastly, the researchers found that the risk genotype was significantly associated with a lower adult IQ. Those with the highest risk phenotype (T/T) had a mean score of 94.3 on the National Adult Reading Test (NART), compared with scores of 100.4 and 101.9 in the C/T (moderate risk) and C/C (lowest risk) groups, respectively (P <0.05).

“The abnormalities in cortical function seen in individuals with the risk genotype are in agreement with previous studies of subjects with psychotic symptoms showing abnormal medial prefrontal and posterior temporal lobe function and support the view that abnormal integration of frontal and temporal lobe function underlies the development of psychotic symptoms,” the authors write. They note that NRG1 has been found to be associated with the development of psychotic symptoms in other disorders, which they suggest raises the possibility that NRG1 may contribute to the development of psychotic features across traditional diagnostic boundaries.—Jillian Lokere.

Reference:
Hall J, Whalley HC, Job DE, Baig BJ, McIntosh AM, Evans KL, Thomson PA, Porteous DJ, Cunningham-Owens DG, Johnstone EC, Lawrie SM. A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms. Advanced online publication 29 October 2006; doi:10.1038/nn1795. Abstract

 
Comments on News and Primary Papers
Comment by:  Amanda Jayne Law, SRF Advisor
Submitted 8 November 2006 Posted 8 November 2006

Convergent evidence supporting the role of a schizophrenia-associated polymorphic variant in the NRG1 gene (SNP8NRG1243177) with the regulation of cortical function and the development of psychosis
The study of Hall and colleagues describes association of a schizophrenia-related polymorphism in the NRG1 gene promoter (SNP8NRG1243177) with cortical and cognitive dysfunction and the emergence of psychotic symptoms in young individuals at high genetic risk for developing schizophrenia. We have previously demonstrated that the same polymorphism (SNP8NRG1243177) and a 22kb risk haplotype, including this SNP, predicts transcription levels of a novel isoform of the NRG1 gene (Type IV) in the brain of patients with schizophrenia (Law et al., 2006; see SRF related news story). The SNP resides in the NRG1 promoter region for the novel E187 exon (Type IV) and our investigations indicate that the SNP is central to a regulatory...  Read more


View all comments by Amanda Jayne Law

Comment by:  Nicholas Stefanis
Submitted 16 November 2006 Posted 16 November 2006

The readers might find our results (now in press) interesting in the context of the brilliant work by Law and colleaguesLaw et al (2006)and now Hall and colleagues. We examined the potential impact of 18 single nucleotide polymorphisms (SNPs) within the DTNBP1, NRG1, DAOA/G32 and DAAO genes, on cognition and self-rated schizotypy, in a representative population of 2,243 young male military conscripts. Single SNP and haplotype associations were evaluated. The risk allele of functional SNP8NRG243177 was associated with reduced spatial working memory capacity.

This is of particular interest since it has recently been reported that SNP8NRG243177 is a functional polymorphism, the risk allele (T) predicting higher levels of type IV NRG1 mRNA expression (Law et al., 2006), and associated with lower prefrontal (and temporal) activation and development of psychotic symptoms in high risk individuals for schizophrenia (  Read more


View all comments by Nicholas Stefanis
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