N. Smyrnis

Impact of Schizophrenia Candidate Genes on Schizotypy and Cognitive Endophenotypes at the Population Level

BACKGROUND Aspects of cognitive function and schizotypy have been proposed as potential endophenotypes for schizophrenia. It is unknown whether the expression of these endophenotypes at the population level is modulated by the genetic variability of candidate susceptibility genes for schizophrenia. METHODS 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 2243 young male military conscripts. Single SNP and haplotype associations were evaluated. RESULTS The DTNBP1 SNPs rs2619522 and rs760761 exhibited several single marker associations, the minor alleles being associated with lower attention capacity but also a decrease in positive and paranoid schizotypy scores. The DTNBP1 haplotype load had borderline associations with nonverbal IQ, paranoid schizotypy, and sustained attention. For individual NRG1 polymorphisms, isolated but weak signals of association were noted with sustained attention and working memory but not schizotypy. The risk allele of functional SNP8NRG243177 was associated with reduced spatial working memory capacity. An isolated effect of DAAO haplotype variability was noted on negative and disorganization schizotypy. No convincing association of DAOA/G32 variability was detected. CONCLUSIONS The DTNBP1 and, less so, NRG1 and DAAO variants might exert gene-specific modulating effects on schizophrenia endophenotypes at the population level.

The antisaccade task in a sample of 2,006 young males: II. Effects of task parameters

Abstract. Antisaccade performance was investigated in a sample of 2,006 young males as part of a large epidemiological study investigating psychosis proneness. This report summarizes the effects of task parameters on performance using a sample of 55,678 antisaccade trials collected from a subpopulation of 947 individuals. Neither the amplitude nor the latency of an error prosaccade in the antisaccade task was correlated with the latency of the ensuing corrective antisaccade that almost always followed an error. However, the latency of the corrective antisaccade decreased with increasing stimulus distance. Concerning the effects of specific task parameters, trials with stimuli closer to the central fixation point and trials preceded by shorter fixation intervals resulted in more errors and longer latencies for the antisaccades. Finally, there were learning and fatigue effects reflected mainly in the error rate, which was greater at the beginning and at the end of the 5-min task. We used a model to predict whether an error or a correct antisaccade would follow a particular trial. All task parameters were significant predictors of the trial outcome but their power was negligible. However, when modeled alone, response latency of the first movement predicted 40% of errors. In particular, the smaller this latency was, the higher the probability of an error. These findings are discussed in light of current hypotheses on antisaccade production mechanisms involving mainly the superior colliculus.

Association of RGS4 variants with schizotypy and cognitive endophenotypes at the population level

BackgroundWhile association studies on schizophrenia show conflicting results regarding the importance of the regulator of the G-protein signaling 4 (RGS4) gene, recent work suggests that RGS4 may impact on the structural and functional integrity of the prefrontal cortex. We aimed to study associations of common RGS4 variants with prefrontal dependent cognitive performance and schizotypy endophenotypes at the population level.MethodsFour RGS4 single nucleotide polymorphisms (SNP1 [rs10917670], SNP4 [rs951436], SNP7 [rs951439], and SNP18 [rs2661319]) and their haplotypes were selected. Their associations with self-rated schizotypy (SPQ), vigilance, verbal, spatial working memory and antisaccade eye performance were tested with regressions in a representative population of 2,243 young male military conscripts.ResultsSNP4 was associated with negative schizotypy (higher SPQ negative factor for common T allele, p = 0.009; p = 0.031 for differences across genotypes) and a similar trend was seen also for common A allele of SNP18 (p = 0.039 for allele-load model; but p = 0.12 for genotype differences). Haplotype analyses showed a similar pattern with a dose-response for the most common haplotype (GGGG) on the negative schizotypy score with or without adjustment for age, IQ and their interaction (p = 0.011 and p = 0.024, respectively). There was no clear evidence for any association of the RGS4 variants with cognitive endophenotypes, except for an isolated effect of SNP18 on antisaccade error rate (p = 0.028 for allele-load model).ConclusionCommon RGS4 variants were associated with negative schizotypal personality traits amongst a large cohort of young healthy individuals. In accordance with recent findings, this may suggest that RGS4 variants impact on the functional integrity of the prefrontal cortex, thus increasing susceptibility for psychotic spectrum disorders.

Mixed handedness is associated with the Disorganization dimension of schizotypy in a young male population

Within the ASPIS (Athens Study of Psychosis Proneness and Incidence of Schizophrenia) we sought out to examine in accordance with previous reports if a deviation from dextrality is associated with an augmented endorsement of self rated schizotypal personality traits in a large population of 1129 young male army recruits. Schizotypal traits were assessed using the Schizotypal Personality Questionnaire and hand preference membership was determined by applying stringent criteria derived from the Annett Handedness Questionnaire and the Porac-Coren questionnaire of lateral preferences. By adopting three different definitions of hand preference membership, we confirmed an association between mixed handedness and increased schizotypal personality traits, and in particular with Disorganization schizotypy that encompasses aspects of self perceived difficulties in verbal communication. Non-verbal cognitive ability, as indexed by measurement of non-verbal IQ, sustained attention and working memory was not associated with hand preference. We argue that a deviation from normal cerebral lateralization, as indexed by mixed handedness, is associated with mild sub clinical language dysfunction, rather than non-verbal cognitive ability, and this might be relevant to the expression of psychosis phenotype.

Effects of direction on saccadic performance in relation to lateral preferences

A sample of 676 healthy young males performed visually guided saccades and antisaccades and completed the Porac-Coren questionnaire measuring lateral preferences. There was no difference in mean latency between rightward versus leftward saccades or for saccades executed in the left versus right hemispace. There was also no right/left asymmetry for individuals with left or right dominance as assessed by the lateral preferences questionnaire. The same results were observed for the latency of antisaccades and for the error rate in the antisaccade task. Finally, we did not confirm any substantial subpopulation of individuals with idiosyncratic left/right latency asymmetries that persisted both in the saccade and antisaccade task. These results suggest that neither latency nor antisaccade error rate are good indicators of lateral preferences in these tasks. Other oculomotor tasks might be more sensitive to hemifield differences, or cerebral hemispheric asymmetry is not present at the level of cortical organization of saccades and antisaccades.

Shared variance of oculomotor phenotypes in a large sample of healthy young men

This study used canonical correlation analysis to investigate patterns of shared variance between parameters measured in seven different occulomotor function tasks, namely the visually guided saccade task, the antisaccade task, the closed-loop smooth-pursuit task, the open-loop smooth-pursuit task, and three active visual fixation tasks. These tasks were performed by 2130 young army recruits. Only a small percentage (1–10%) of shared variance existed between sets of parameters for all oculomotor function tasks measured. The most correlated tasks were the visually guided saccade and the antisaccade. The first common factor correlated with speed of performance between these tasks (latency), while the second and third correlated with accuracy of performance. Better performance in active visual fixation tasks correlated with better performance accuracy (lower error rate) and increased speed (lower latency) in the antisaccade and saccade tasks as well as better performance in the closed-loop smooth-pursuit task (increase in gain and decrease in the rate of unwanted saccades during pursuit). Better performance in the closed-loop smooth-pursuit task (increased gain and decreased number of unwanted saccades) also correlated with increased accuracy and increased speed of performing saccades and antisaccades. Finally, the open-loop fixation task had no correlation with all other oculomotor tasks except for a very weak negative correlation with the closed-loop pursuit task where better performance (increased gain) in one correlated with worse performance (decreased gain) in the other. The results of this analysis showed that a small percentage of variance is shared among different oculomotor function tasks. The structure of this shared variance could be used to derive common oculomotor function indices to study their relation to genetic and other sources of inter-subject variation.