Schizophrenia-related RGS4 gene variations specifically disrupt prefrontal control of saccadic eye movements E. Kattoulas 1,2 , N. C. Stefanis 1,2 , D. Avramopoulos 3 , C. N. Stefanis 1 , I. Evdokimidis 4 and N. Smyrnis 1,2 * 1 University Mental Health Research Institute, National and Kapodistrian University of Athens, Athens, Greece 2 1st Psychiatry Department, National and Kapodistrian University of Athens, Medical School, Eginition Hospital, Athens, Greece 3 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA 4 Neurology Department, National and Kapodistrian University of Athens, Medical School, Eginition Hospital, Athens, Greece Background. The gene encoding the regulator of G-protein signaling subtype 4 (RGS4), located on chromosome 1q23-3, has been proposed as a possible susceptibility gene for schizophrenia and has been specifically linked to prefrontal cortical structural and functional integrity. Method. The effects of four core single nucleotide polymorphisms (SNPs) within the RGS4 gene on oculomotor parameters in a battery of oculomotor tasks (saccade, antisaccade, smooth eye pursuit, fixation) were investigated in a sample of 2243 young male military conscripts. Results. The risk allele of RGS4SNP18 was found to be associated with two variables of antisaccade performance, increased error rate and variation in the correct antisaccade latency. By contrast, the same allele and also the risk allele of RGS4SNP4 led to an improvement in smooth eye pursuit performance (increased gain). Structural equation modeling confirmed that the combined gene variation of RGS4SNP4 and RGS4SNP18 was a significant predictor of antisaccade but not smooth eye pursuit performance. Conclusions. These results provide evidence for a specific effect of schizophrenia-related RGS4 genotype variations to prefrontal dysfunction measured by oculomotor indices of performance in normal individuals, further validating the hypothesis that RGS4 is related to prefrontal dysfunction in schizophrenia. Received 6 September 2010 ; Revised 20 July 2011 ; Accepted 29 July 2011 ; First published online 13 September 2011 Key words : Antisaccade, endophenotypes, oculomotor, saccade, schizophrenia candidate genes, smooth eye pursuit. Introduction Efforts to identify genetic risk factors for schizo- phrenia using linkage and association studies have identified several candidate genes. Among these, the gene encoding the regulator of G protein signaling subtype 4 (RGS4), located on chromosome 1q23-3, has been proposed as a possible susceptibility gene for schizophrenia in a microarray gene expression study (Mirnics et al. 2001) and in association studies (Chowdari et al. 2002). RGS4 belongs to the regulator of G protein signaling family and is the most widely distributed and highly expressed protein of this family in the brain. Binding to G-protein-coupled receptors (GPCRs), it modulates intracellular signaling, thus attenuating the intensity and duration of signal transduction (Watson et al. 1996) for receptors belong- ing to dopamine, gamma-aminobutyric acid (GABA), glutamate and serotonin neurotransmitter systems (Harrison & Weinberger, 2005). The original reports linking RGS4 to schizophrenia have been replicated by several studies (Williams et al. 2004 ; Prasad et al. 2005; So et al. 2008), although the associated alleles often differed, but not by others (Guo et al. 2006 ; Ishiguro et al. 2006). This incon- sistency is discussed in a review by Talkowski et al. (2006), suggesting a modest association between RGS4 polymorphisms and schizophrenia while emphasizing the need for alternative research strategies. The multiple genes and the gene–environment interaction linked to the disorder, in addition to its clinical heterogeneity, might underlie this incon- sistency. In an attempt to overcome the obstacle of clinical heterogeneity, So et al. (2008) focused on the association of RGS4 polymorphisms with phenotypic subgroups of schizophrenia, whereas other studies have tried to link RGS4 polymorphisms to specific * Address for correspondence : N. Smyrnis, M.D., Ph.D., 1st Psychiatry Department, National and Kapodistrian University of Athens, Medical School, Eginition Hospital, 72 V. Sofias Avenue, Athens 11528, Greece. (Email : smyrnis@med.uoa.gr) Psychological Medicine (2012), 42, 757–767. f Cambridge University Press 2011 doi:10.1017/S003329171100167X ORIGINAL ARTICLE