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DISC1 2010—DISC1 and Endophenotypes

As part of our ongoing coverage of DISC1 2010, held 3-6 September 2010, in Edinburgh, the United Kingdom, we bring you a meeting missive from Rosie Walker, a graduate student at the University of Edinburgh.

17 September 2010. The third session of the conference—with David St Clair leading Part two of the Genotype and Phenotype theme—was opened on Saturday afternoon by Daniel Weinberger of the National Institute of Mental Health. Weinberger began by explaining the unique opportunity presented by DISC1 as a window into the brain mechanisms that underlie psychopathology: the DISC1 chromosomal abnormality observed in the Scottish t(1;11) is the only rare chromosomal abnormality that is not associated with any phenotype but psychopathology. Yet progress in understanding the function of DISC1 in the brain has been slow, and the study of DISC1 has been plagued by the same questions that are being asked in the psychiatric genetics field more generally: why have genes for psychiatric illness been so controversial? And why are clinical associations so weak? Weinberger answered both of these questions by stating that “genes do not encode for psychiatric illness,” and emphasized the benefits of studying intermediate phenotypes at the cellular and systems level where greater penetrance and, therefore, larger effect sizes are likely to be observed.

The validity of cognition as an intermediate phenotype for schizophrenia was highlighted using data from a recent collaboration between the NIMH group and Toulopoulou and colleagues at the Institute of Psychiatry, London (2010), which finds that a large proportion of the phenotypic correlation between schizophrenia and cognition is attributable to shared genetic effects. Weinberger proceeded to present results from a series of imaging experiments from his group that have investigated brain activity during working memory tasks. These experiments have revealed differences in hippocampal and prefrontal brain activation between carriers of different alleles of SNPs in DISC1 and other schizophrenia-associated genes (Callicott et al., 2005; Tan et al., 2008), as well as altered coupling between hippocampal and prefrontal regions in carriers of a schizophrenia risk variant in ZNF804A (Esslinger et al., 2009; see SRF related news story). Recent unpublished work from Weinberger's group has found an abnormal pattern of hippocampal and prefrontal coupling during a working memory task in patients with schizophrenia, and a phenotype intermediate between schizophrenic and control subjects in healthy siblings of schizophrenic patients. Decreased phase uncoupling observed in schizophrenic patients and, to a lesser extent, their healthy siblings, suggests that increased interference might diminish working memory function in these individuals.

Moving to intermediate phenotypes at the cellular level, Weinberger stated that genetic risk is ultimately due to cell morphology. In support of this claim, he cited another study from his group (Nakata et al., 2009), in which an altered distribution of short DISC1 transcripts were found in the brains of patients with schizophrenia.

Next to speak was William Hennah of the Academy of Finland. Continuing the theme of “Genotype and Phenotype,” Hennah spoke about genetic studies in the Finnish population. Recent studies in this population have supported the role of DISC1 interactors as risk factors for schizophrenia (Tomppo et al., 2009) and indicated the importance of studying interactions between SNPs for identifying conditional risk variants (Hennah et al., 2009). Further interaction analysis of DISC1 pathway genes is in progress, and unpublished work from Hennah’s group has identified genes, including the lactase (LCT) gene, that interact with specific DISC1 variants to increase levels of anhedonia, a personality trait associated with schizophrenia.

Next, Hennah turned to ongoing work with an obvious clinical application: the association of DISC1 pathway variants with psychoactive drug cessation, which is typically due to adverse side effects. Looking at 10-year prescription data, Hennah has found that cessation of several drugs is associated with variants across genes in the DISC1 pathway. It is hoped that by looking at overlaps between the associated genes, clues to drug functions will be revealed. Whilst these results are from a small sample and must be considered preliminary, they raise the interesting prospect of improved drug efficacy based on analysis of genotype at key markers in DISC1 pathway genes.

In the following talk, Svenja Trossbach of Heinrich-Heine University Düsseldorf, Germany, presented work investigating the link between DISC1 and nicotine. Increased smoking in schizophrenic patients compared to the general population is a well-documented phenomenon, and it has been shown that the schizophrenia-associated deficit in sensory gating, as measured by prepulse inhibition (PPI), can be ameliorated by nicotine (Kumari et al., 1997). It has been proposed that the effect of nicotine on PPI is mediated by α7 nicotinic acetylcholine receptors (α7 nAChR; Suemaru et al., 2004), the expression of which is regulated by neuregulin-1 (NRG1) type 3 (Hancock et al., 2008). Following on from recent work indicating that NRG1 regulates DISC1 (Seshadri et al., 2010; see SRF related news story), Trossbach asked whether there is a direct interaction between DISC1 and nicotine. Pull-down assays in rat hippocampal tissue and pharmacological studies in cultured cells yielded evidence consistent with an interaction. In humans, an antibody raised against the C-terminus of DISC1 indicated decreased DISC1 in peripheral blood mononuclear cells (PBMC) of schizophrenic patients compared with healthy controls. This decrease was further exacerbated by smoking, with schizophrenic smokers showing the lowest level of immunoreactivity. Trossbach concluded by stating that nicotine and the activity of nicotinic acetylcholine receptors has an effect on DISC1 expression, and raised the interesting prospect of using detection of DISC1 expression in PBMC as a biomarker for schizophrenia.

The session was brought to a close by Xianjin Zhou of the University of California, San Diego. In a recent publication, Zhou and colleagues identified a novel gene, named Boymaw, on chromosome 11 that is disrupted by the t(1;11) translocation found in the original Scottish family (Zhou et al., 2010). DISC1-Boymaw fusion transcripts generated to mimic the effect of the t(1;11) translocation were found to produce insoluble proteins in in vitro cell transfections, reminiscent of the insoluble DISC1 proteins found in the postmortem brains of some patients with schizophrenia (Leliveld et al., 2008). Zhou and colleagues are now in the process of generating chimeric mice carrying a conditional knock-in of the DISC1-Boymaw fusion gene, with the hope of producing a general model for assessing the consequences of insoluble DISC1.—Rosie Walker.

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