Elsevier

NeuroImage

Volume 45, Issue 3, 15 April 2009, Pages 1002-1008
NeuroImage

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

https://doi.org/10.1016/j.neuroimage.2008.12.054Get rights and content

Abstract

G72 is a vulnerability gene for schizophrenia and affective psychosis, disorders that are characterized by deficits in working memory. In the present study we investigated whether the G72 genotype influences verbal and spatial working memory functions in healthy individuals. Working memory was assessed at the behavioural level in 423 subjects using the spatial span of the Wechsler Memory Scale (spatial working memory) and the letter–number-span test (verbal working memory). In a sub-sample of 83 subjects, we assessed working memory functions also at the neural level using functional magnetic resonance imaging during a classical letter variant of the n-back task.

Unexpectedly the high risk allele carriers performed better in the verbal working memory task than the other subjects. These behavioural differences were accompanied by brain activation differences in the right parahippocampus, a brain region that plays a major role in schizophrenia and affective disorders. The high risk variant of a vulnerability gene therefore does not necessarily have to negatively affect cognitive abilities per se, but may even have beneficial effects on cognitive functions in the non-affected population.

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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