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 transcription factor binding domain. We previously suggested that a potential molecular mechanism behind the clinical association of NRG1 with schizophrenia (at least in the 5’ region of the gene) involves altered transcriptional regulation of the gene, which modifies to a small degree and in an isoform-specific fashion, the efficiency of NRG1 signaling effects on neural development and plasticity. We predicted that such effects may translate into altered adult brain function.

With this in mind, the study of Hall and colleagues provides a remarkable level of functional convergence suggesting a potential link between a molecular phenotype related to genetic risk at this loci (i.e., increased transcriptional regulation of the novel Type IV isoform, Law et al., 2006) and abnormal cortical development, function, and the subsequent manifestation of psychotic symptoms.

The major objective of the study was to determine the relationship between previously identified genetic variants in the 5’ region of NRG1 (Stefansson et al., 2002; see also Harrison and Law, 2006) with aspects of the schizophrenia phenotype (including decreased IQ, altered cortical function, and psychosis) in individuals who are at high risk of developing the disorder. Subjects were followed throughout the course of the study or until they developed schizophrenia. It is noteworthy that the incidence rate of developing schizophrenia was highest in subjects homozygous for the risk (T) allele at NRG1243177 (25 percent). Conversely, the occurrence of schizophrenia in non-risk C/C individuals was lower (15 percent), but still present, demonstrating the complex heterogeneous nature of the disease.

The study was performed on a modest sample of 79 high-risk individuals, 63 of whom fMRI data was available for. Firstly, brain activation patterns were determined by fMRI whilst individuals were performing the Hayling sentence completion task. Subjects who were homozygous for the risk T allele (T/T) at SNP8NRG1243177 exhibited decreased activation of Brodmann area 9 and the right temporo-occipital junction (Brodmann areas 39 and 19) when the activation during the task was compared to the resting state. However, unlike the medial prefrontal cortex, the difference in activation of the right temporal-occipital junction derived from the fact that T/T individuals had a “higher” resting activity compared to C/C individuals (as stated by the authors). Based on this observation, it is difficult to interpret which phenotype, in terms of cortical activation in this region, genetic risk at the allele is associated with—that is, is the risk variant associated with an overactive right temporo-occipital cortex at rest, or with decreased ability to further activate the region during demand?

In the supplementary notes, the authors address this issue, stating that a failure to deactivate the temporal cortex during rest may suggest that frontotemporal activity is disrupted in individuals homozygous for the T allele at SNP8NRG1243177. Furthermore, based on our studies, it would be important to see if genetic risk at SNP8NRG1243177 predicts hippocampal activation during a task that activates this area, allowing one to link the molecular changes in the hippocampus in schizophrenia, related to genetic risk at this SNP, to an outcome measure of brain function. Conversely, it would also be of use to determine whether NRG1 Type IV expression is altered in the brain areas implicated by Hall and colleagues.

Importantly, the study also shows that the genotype effects at SNP8NRG1243177 on cortical function are not related to medication status (all subjects were medication-free). Secondly, Hall and colleagues investigated the effects of the SNP8NRG1243177 risk allele on the development of psychotic symptoms in high-risk individuals. In a remarkable observation, 100 percent of individuals who had the risk T/T genotype developed psychotic symptoms, compared to less than 50 percent of C/C individuals, although the small sample size must be kept in mind. One interesting observation that is not readily apparent in the study is the fact that of the 12 T/T individuals who developed psychotic symptoms, only three of those (25 percent) developed schizophrenia before the end of the study. This may be due to the fact that others later went on to develop the disorder or that they developed other complex mental illnesses which include psychosis, such as bipolar disorder. (This is not clear from the study.) The association of genetic risk in the NRG1 gene and psychotic symptom development is consistent with the fact that genetic risk at NRG1 has been linked to psychosis in other brain diseases such as bipolar disorder and Alzheimer’s disease (see Harrison and Law, 2006). Finally, and perhaps most compelling, there is the observation that genetic risk at SNP8NRG1243177 is related to decreased IQ (measured by NART) in high-risk individuals.

Overall, the study of Hall and colleagues provides novel evidence that genetic variation in the NRG1 promoter, in particular a genetic variant that predicts altered expression of the NRG1 gene in the brain in schizophrenia (Law et al., 2006), is associated with abnormalities in cortical function and cognition and contributes to psychotic symptoms in individuals at high risk of developing the disease.

View all comments by Amanda Jayne Law

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 (Hall et al., 2006). If not a chance finding, our result constitutes the first independent confirmation that functional SNP8NRG243177 impacts aspects of human prefrontal brain function. Since spatial working deficits constitute an effective endophenotype for schizophrenia, this finding also suggests a mechanism by which this NRG1 variant may confer risk for the disorder at an information processing level. In contrast to Hall and colleagues, no association of SNP8NRG243177 with psychotic-like symptoms or IQ was detected in this study.

References:
Nicholas C. Stefanis, Thomas A. Trikalinos, Dimitrios Avramopoulos, Nikos Smyrnis, Ioannis Evdokimidis, Evangelia E. Ntzani, John P. Ioannidis and Costas N. Stefanis. Impact of schizophrenia candidate genes on schizotypy and cognitive endophenotypes at the population level. Biological Psychiatry (in press).

View all comments by Nicholas Stefanis