A putative high risk diplotype of the G72 gene is in healthy individuals associated with better performance in working memory functions and altered brain activity in the medial temporal lobe
Introduction
Although bipolar disorder, major depression and schizophrenia are defined as distinct and exclusive diagnostic entities, they show an overlap of symptoms (Berrettini, 2000). Hence, the separation of psychiatric syndromes into etiologically homogenous subtypes is currently under debate (Craddock et al., 2006, Craddock and Owen, 2005). Diagnostic boundaries are therefore rather justified by clinical convenience than by neurobiological foundation (Gottesman and Gould, 2003).
Cognitive deficits are present in schizophrenia and affective disorders. Particularly working memory deficits play a central role in schizophrenia (Daban et al., 2005, Glahn et al., 2003, Silver et al., 2003), but have also been reported for patients with bipolar disorder (Ferrier et al., 1999, McGrath et al., 2001, Sweeney et al., 2000) and, to a lesser extent, major depression (Beats et al., 1996, Ravnkilde et al., 2002). In schizophrenia and bipolar disorder working memory deficits have been found to be associated with genetic vulnerability and certain genotypes, making them promising endophenotypes, i.e. mediators between genotype and clinical phenotype (Gottesman and Gould, 2003).
Schizophrenia and affective disorders are caused by a combination of genetic predispositions and environmental triggers. The genetic vulnerability of an individual evolves from addition or potentiation of a specific cluster of risk genes (Harrison and Weinberger, 2005, Lang et al., 2007). Linkage and association studies suggest that a genetic vulnerability does not mandatory lead to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or season of birth have been identified as risk factors alone or in combination with genetic vulnerability (Lang et al., 2007).
Recently, several susceptibility genes for affective disorders and schizophrenia have been identified (for reviews, cf. Chubb et al., 2008, Harrison and Weinberger, 2005, Owen et al., 2005b, Smoller and Gardner-Schuster, 2007). Studies on DTNBP1 (dysbindin), COMT, BDNF, DISC1, NRG1, and G72 suggested a great genetic overlap across affective disorders and schizophrenia (Craddock et al., 2005Craddock et al., 2006, Craddock and Owen, 2005, Green et al., 2005, Maier et al., 2005, Williams et al., 2006). G72 (recently named d-amino acid oxidase activator, DAOA) is among the most frequently replicated vulnerability genes for schizophrenia (Addington et al., 2004, Chumakov et al., 2002, Li and He, 2007, Schumacher et al., 2004) and bipolar disorder (Addington et al., 2004, Prata et al., 2008, Schumacher et al., 2004) (for review, cf. Detera-Wadleigh and McMahon, 2006). Recently, G72 has also been associated with major depression (Rietschel et al., 2008). The association of variation in G72 with affective disorders and schizophrenia provides support for the hypothesis that they share some of their etiological background. Although the association between gene and disorders is established, its functional relevance is still unclear.
Hence, the classification of affective disorders and schizophrenia on the basis of overt phenotypes might not be optimal for a genetic dissection of these complex diseases. Furthermore, as the genetic overlap between affective disorders and schizophrenia shows a weakness of specificity of the current classification system, functional neuroimaging techniques may provide a sensitive measure to bridge the neurobiology of genes and behaviour, since brain activation patterns might be nearer to the actual neurobiology of the gene than cognitive measures alone (Lanzenberger and Kasper, 2005, Lawrie et al., 2008).
In the present study we investigated whether behavioural measures as well as neural correlates of working memory are differentially influenced by genetic alteration in the G72 gene in healthy subjects. All subjects were genotyped for two G72 single nucleotide polymorphisms (SNPs), M23 and M24. The M23–M24 haplotypes C–T and T–A have recently been associated with schizophrenia, bipolar disorder and major depression (Rietschel et al., 2008). The neural correlates of working memory were assessed by fMRI using a variant of an n-back task. Here, subjects are asked to monitor the identity or location of a series of verbal or non-verbal stimuli and to indicate whether the currently presented stimulus is the same as the one presented n trials previously. Differences in brain activation were expected in key regions underlying working memory performance, such as prefrontal cortex, parietal brain areas and medial temporal lobe (MTL) structures (Owen et al., 2005a).
Section snippets
Behavioural sample
The subjects were recruited through postings at the University of Aachen, advertisements in local newspapers and an e-mail sent to all students of the University of Aachen. 423 subjects (214 men, 209 women) were included in the present study. Inclusion criteria were age (18–55 years), right-handedness (as assessed by the Edinburgh Inventory, Oldfield, 1971), no psychiatric disorders according to ICD-10 and Western- or Middle European descent. The subjects' characteristics are given in Table 1.
Behavioural sample
In the whole sample, the ANOVA showed a main effect of G72 status on verbal working memory (F = 6.636, p < 0.001), but not on spatial working memory (F = 2.585, p = 0.077). Post-hoc t-tests revealed that the group differences in verbal working memory were caused by an increased performance of the high risk group compared to both other groups (Fig. 1).
Behavioural data
As expected, analyses of behavioural data of the fMRI task (i.e. number of correct responses, false alarms, and reaction times) revealed no significant
Discussion
In the present study we investigated the effect of G72 genotype status on working memory in a large sample of healthy subjects. Our results show that G72 status influences verbal working memory performance, with the high risk allele carriers scoring better than the other groups. The behavioural differences were accompanied by differences in fMRI measured brain activity in the right parahippocampal gyrus, with the high risk allele carriers showing significantly more deactivation than the other
Acknowledgments
This work was supported by the Federal Ministry of Education and Research (Brain Imaging Centre West, 01GO0204). AJ and SK were supported by the Federal Ministry of Education and Research (01GW0751).
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2012, NeuropharmacologyCitation Excerpt :This may indicate that G72 affects brain functions and psychiatric symptoms across traditional clinical categories. Indeed, several fMRI studies examining healthy individuals and schizophrenia patients have found that variation in the G72 gene significantly influences cognitive performance, affecting verbal fluency, memory, attention and the recruitment of the hippocampus and prefrontal cortex (Goldberg et al., 2006; Hall et al., 2008; Opgen-Rhein et al., 2008; Jansen et al., 2009a,b; Krug et al., 2010; but see Jansen et al., 2010). Overall, G72 and DAO variants have relatively small effects on schizophrenia risk, consistent with the modest effect sizes observed for individual genes in complex disorders like schizophrenia (Manolio et al., 2009; Gogos and Gerber, 2006).
S100B gene polymorphisms predict prefrontal spatial function in both schizophrenia patients and healthy individuals
2012, Schizophrenia ResearchCitation Excerpt :For example, behavioral genetics studies found that 7%–30% of the genetic variance in working memory was due to modality-specific factors (i.e., spatial vs. verbal) (Ando et al., 2001). Similarly, molecular genetics studies have found that spatial working memory and verbal working memory have different molecular genetic bases (Jansen et al., 2009). Along the same line, although the ANT and the Stroop task both assess the executive control of attention, they have different neural bases (Fan et al., 2003), attention processing (Chajut et al., 2009), and heritability (Breton et al., 2011).
Intermediate phenotypes in psychiatric disorders
2011, Current Opinion in Genetics and DevelopmentCitation Excerpt :For the most part, unaffected relatives of patients with schizophrenia show qualitatively similar abnormal engagement of prefrontal cortex (PFC), thalamus, hippocampus–parahippocampus formation (HF) and inferior parietal lobule — especially in the right hemisphere [14,16,17,18•,19,20••] (Supplementary Table 1A). Activation of these regions and of the circuit involving them has been studied using the ‘imaging genetic’ approach for several putative schizophrenia associated genes [8–11,21–34,30••] (Supplementary Table 2A). Interestingly, the first GWA positive gene, ZNF804A, has not shown association with this phenotype per se [10••] (but see below).