Common genetic variation and schizophrenia polygenic risk influence neurocognitive performance in young adulthood.

Neurocognitive abilities constitute complex traits with considerable heritability. Impaired neurocognition is typically observed in schizophrenia (SZ), whereas convergent evidence has shown shared genetic determinants between neurocognition and SZ. Here, we report a genome-wide association study (GWAS) on neuropsychological and oculomotor traits, linked to SZ, in a general population sample of healthy young males (n = 1079). Follow-up genotyping was performed in an identically phenotyped internal sample (n = 738) and an independent cohort of young males with comparable neuropsychological measures (n = 825). Heritability estimates were determined based on genome-wide single-nucleotide polymorphisms (SNPs) and potential regulatory effects on gene expression were assessed in human brain. Correlations with general cognitive ability and SZ risk polygenic scores were tested utilizing meta-analysis GWAS results by the Cognitive Genomics Consortium (COGENT) and the Psychiatric Genomics Consortium (PGC-SZ). The GWAS results implicated biologically relevant genetic loci encoding protein targets involved in synaptic neurotransmission, although no robust individual replication was detected and thus additional validation is required. Secondary permutation-based analysis revealed an excess of strongly associated loci among GWAS top-ranked signals for verbal working memory (WM) and antisaccade intra-subject reaction time variability (empirical P < 0.001), suggesting multiple true-positive single-SNP associations. Substantial heritability was observed for WM performance. Further, sustained attention/vigilance and WM were suggestively correlated with both COGENT and PGC-SZ derived polygenic scores. Overall, these results imply that common genetic variation explains some of the variability in neurocognitive functioning among young adults, particularly WM, and provide supportive evidence that increased SZ genetic risk predicts neurocognitive fluctuations in the general population.

Predictive smooth eye pursuit in a population of young men: I. Effects of age, IQ, oculomotor and cognitive tasks.

Smooth eye pursuit is believed to involve the integration of an extraretinal signal formed by an internal representation of the moving target and a retinal signal using the visual feedback to evaluate performance. A variation of the smooth eye pursuit paradigm (in which the moving target is occluded for a short period of time and subjects are asked to continue tracking) designed to isolate the predictive processes that drive the extraretinal signal was performed by 1,187 young men. The latency to the onset of change in pursuit speed, the time of decelerating eye-movement speed and the steady state residual gain were measured for each subject and correlated with measures of other oculomotor (closed-loop smooth eye pursuit, saccade, antisaccade, active fixation) and cognitive tasks (measuring sustained attention and working memory). Deceleration time increased with increasing age, while education, general IQ and cognitive variables had no effect on predictive pursuit performance. Predictive pursuit indices were correlated to those of closed-loop pursuit and antisaccade performance, but these correlations were very weak except for a positive correlation of residual gain to saccade frequency in the fixation task with distracters. This correlation suggested that the maintenance of active fixation is negatively correlated with the ability to maintain predictive pursuit speed. In conclusion, this study presents predictive pursuit performance in a large sample of apparently healthy individuals. Surprisingly, predictive pursuit was weakly if at all related to closed-loop pursuit or other oculomotor and cognitive tasks, supporting the usefulness of this phenotype in the study of frontal lobe integrity in normal and patient populations.

Predictive smooth eye pursuit in a population of young men: II. Effects of schizotypy, anxiety and depression.

Smooth pursuit eye movement dysfunction is considered to be a valid schizophrenia endophenotype. Recent studies have tried to refine the phenotype in order to identify the specific neurophysiological deficits associated with schizophrenia. We used a variation of the smooth eye pursuit paradigm, during which the moving target is occluded for a short period of time and subjects are asked to continue tracking. This is designed to isolate the predictive processes that drive the extraretinal signal, a process previously reported to be defective in schizophrenia patients as well as their healthy relatives. In the current study, we investigated the relationship between predictive pursuit performance indices and age, education, non-verbal IQ, schizotypy and state anxiety, depression in 795 young Greek military conscripts. State anxiety was related to better predictive pursuit performance (increase in residual pursuit gain), while disorganized schizotypy was related to deficient predictive pursuit performance (decreased residual gain). This effect was independent of the effect of disorganized schizotypy on other oculomotor functions supporting the hypothesis that predictive pursuit might be specifically affected in schizophrenia spectrum disorders and could be considered as a distinct oculomotor endophenotype.

Interaction of schizophrenia and chronic cannabis use on reward anticipation sensitivity.

Chronic cannabis use and schizophrenia are both thought to affect reward processing. While behavioural and neural effects on reward processing have been investigated in both conditions, their interaction has not been studied, although chronic cannabis use is common among these patients. In the present study eighty-nine participants divided into four groups (control chronic cannabis users and non-users; schizophrenia patient cannabis users and non-users) performed a two-choice decision task, preceded by monetary cues (high/low reward/punishment or neutral), while being scanned using functional magnetic resonance imaging. Reward and punishment anticipation resulted in activation of regions of interest including the thalamus, striatum, amygdala and insula. Chronic cannabis use and schizophrenia had opposing effects on reward anticipation sensitivity. More specifically control users and patient non-users showed faster behavioural responses and increased activity in anterior/posterior insula for high magnitude cues compared to control non-users and patient users. The same interaction pattern was observed in the activation of the right thalamus for reward versus punishment cues. This study provided evidence for interaction of chronic cannabis use and schizophrenia on reward processing and highlights the need for future research addressing the significance of this interaction for the pathophysiology of these conditions and its clinical consequences.

Monitoring antisaccades: inter-individual differences in cognitive control and the influence of COMT and DRD4 genotype variations.

Conscious monitoring of behavior is an essential control function for adaptation and learning. Antisaccade performance was investigated in a large sample of young healthy men in two tasks, one that required conscious error monitoring and one that did not. Conscious error monitoring did not lead to changes in error rate between the two tasks, while other antisaccade parameters were significantly modulated. Application of signal detection theory showed a large inter-individual variability in error detection sensitivity: the majority of individuals were unable to monitor antisaccade errors (chance error detection group), while a minority that successfully monitored their errors (non-chance error detection group) were worse in antisaccade performance in both tasks. These results were explained by the hypothesis of two modes of antisaccade processing favored by each one of the two groups: a mode of conscious cortical cognitive control leading to error monitoring, worse performance and no post-error adaptation and a mode of non-conscious subcortical control leading to chance error monitoring, post-error slowing and better performance of the antisaccade task. This hypothesis was corroborated by the results of the genotype analysis. Error-monitoring sensitivity in the non-chance error detection group was modulated by COMT genotype variations that in turn did not have an effect on error rate. On the other hand, DRD4 genotype variations were related to differences in antisaccade error rate while not affecting error-monitoring sensitivity.

Perceived social stigma, self-concept, and self-stigmatization of patient with schizophrenia.

The advent of community-based mental health care in Greece emphasized clinicians' need to understand patients' attitudes and their experience of their illness. A 42-item self-administered questionnaire (Self-Stigmatization Questionnaire) with flexible format was designed and administered to 150 outpatients with schizophrenia who fulfilled the criteria for inclusion in the vocational rehabilitation program where the study took place. The patients participated voluntarily. Multivariate regression models were applied to each item to assess the degree of patients' self-stigmatization experience as well as the effect of potential factors such as age, sex, psychopathologic condition, hospitalization, and duration of illness. The options selected by the patients revealed stigmatized attitudes in most items. The odds of selecting these options were mainly influenced by the severity of the patients' psychopathologic condition and the duration of illness and less by sex, age, and hospitalization.

Familial and socioeconomic contributions to premorbid functioning in psychosis: Impact on age at onset and treatment response.

BACKGROUND: Premorbid adjustment (PA) abnormalities in psychotic disorders are associated with an earlier age at onset (AAO) and unfavorable clinical outcomes, including treatment resistance. Prior family studies suggest that familial liability, likely reflecting increased genetic risk, and socioeconomic status (SES) contribute to premorbid maladjustment. However, their joint effect possibly indicating gene-environment interaction has not been evaluated. METHODS: We examined whether family history of psychosis (FHP) and parental SES may predict PA and AAO in unrelated cases with first-episode psychosis (n = 108) and schizophrenia (n = 104). Premorbid academic and social functioning domains during childhood and early adolescence were retrospectively assessed. Regression analyses were performed to investigate main effects of FHP and parental SES, as well as their interaction. The relationships between PA, AAO, and response to antipsychotic medication were also explored. RESULTS: Positive FHP associated with academic PA difficulties and importantly interacted with parental SES to moderate social PA during childhood (interaction p = 0.024). Positive FHP and parental SES did not predict differences in AAO. Nevertheless, an earlier AAO was observed among cases with worse social PA in childhood (ß = -0.20; p = 0.005) and early adolescence (ß = -0.19; p = 0.007). Further, confirming evidence emerged for an association between deficient childhood social PA and poor treatment response (p = 0.04). CONCLUSIONS: Familial risk for psychosis may interact with parental socioeconomic position influencing social PA in childhood. In addition, this study supports the link between social PA deviations, early psychosis onset, and treatment resistance, which highlights premorbid social functioning as a promising clinical indicator.

Factorial composition of the Aggression Questionnaire: a multi-sample study in Greek adults.

The primary aim of the current article was the evaluation of the factorial composition of the Aggression Questionnaire (AQ(29)) in the Greek population. The translated questionnaire was administered to the following three heterogeneous adult samples: a general population sample from Athens, a sample of young male conscripts and a sample of individuals facing problems related to substance use. Factor analysis highlighted a structure similar to the one proposed by Buss and Perry [Buss, A.F., Perry, M., 1992. The Aggression Questionnaire. Journal of Personality and Social Psychology 63, 452-459]. However, the refined 12-item version of Bryant and Smith [Bryant, F.B., Smith, B.D., 2001. Refining the architecture of aggression: a measurement model for the Buss-Perry Aggression Questionnaire. Journal of Research in Personality 35, 138-167] provided a better fit to our data. Therefore, the refined model was implemented in further analysis. Multiple group confirmatory factor analysis was applied in order to assess the variability of the 12-item AQ across gender and samples. The percentage of factor loading invariance between males and females and across the three samples defined above was high (higher than 75%). The reliability (internal consistency) of the scale was satisfactory in all cases. Content validity of the 12-item AQ was confirmed by comparison with the Symptom Check-List 90 Revised.

Larger variability of saccadic reaction times in schizophrenia patients.

Slower mean reaction time (RT), known as psychomotor slowing, is well documented in patients with schizophrenia. Fewer studies have shown increased variability of RT in these patients suggesting a basic difference in the distribution of RT. In this study median RT and its variability were measured for visually guided saccades performed by 53 patients and 1089 control subjects. Then average cumulative RT distributions were derived for each group and the RT distribution for each group was modeled using a decision signal rising linearly to a threshold signaling the beginning of the visually guided saccade. There was a small increase in the median RT for patients while their RTs were much more variable from trial to trial leading to a difference in the average RT distribution of the patient group. The model application led to the conclusion that this difference in the distribution of RT for patients could be attributed to a basic difference in information processing leading to the decision to move the eyes to the visually presented target. This information-processing difference could be the result of a difference in the build-up of neuronal activity involved in the generation of visually guided saccades in the frontal cortex.

The effect of change in clinical state on eye movement dysfunction in schizophrenia.

Measures of eye movement dysfunction have been considered as candidate endophenotypes for the study of genetic liability in schizophrenia. In this respect it is crucial to confirm a clinical state independentce of these measures. Twenty people with DSM-IV schizophrenia were assessed using a battery of oculomotor tasks in the acute phase of their disorder without being treated with antipsychotic medication and then again in the remission phase under treatment with antipsychotic medication. The saccade latency in the saccade task, the error rate and antisaccade latency in the antisaccade task, and the frequency of unwanted saccades in the active fixation task were stable in time both at the group level and within each individual, showing no relation to the significant improvement in different psychopathological dimensions of these patients. The root mean square error, gain and saccade frequency in the pursuit task were not stable over time, although again this instability was not related to the changes in psychopathological status of these patients. Finally, the saccade frequency in the active fixation task with distracters was not stable in time and was correlated with changes in specific dimensions of psychopathology. These results provide further evidence that saccade and smooth eye pursuit dysfunction measures are not affected by the substantial change in the clinical state of schizophrenia from the acute phase to remission, and strengthen the current view that they can be used as endophenotypes. On the other hand, active fixation might be state-dependent adding to the evidence against its use as a candidate endophenotype in schizophrenia.

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

BACKGROUND: While 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. METHODS: Four 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. RESULTS: SNP4 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). CONCLUSION: Common 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.

Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene-stress interaction.

This article presents evidence suggesting that psychosocial stress may increase risk for psychosis, especially in the case of cumulative exposure. A heuristically useful framework to study the underlying mechanisms is the concept of "behavioral sensitization" that stipulates that exposure to psychosocial stress--such as life events, childhood trauma, or discriminatory experiences--may progressively increase the behavioral and biological response to subsequent exposures. The neurobiological substrate of sensitization may involve dysregulation of the hypothalamus-pituitary-adrenal axis, contributing to a hypothesized final common pathway of dopamine sensitization in mesolimbic areas and increased stress-induced striatal dopamine release. It is argued that, in order to reconcile genetic and environmental influences on the development of psychosis, gene-environment interactions may be an important mechanism in explaining between-subject differences in risk following (cumulative) exposure to psychosocial stress. To date, most studies suggestive of gene-stress interaction have used proxy measures for genetic vulnerability such as a family history of psychosis; studies investigating interactions between molecular genetic measures and psychosocial stressors are still relatively scarce. Preliminary evidence suggests that polymorphisms within the catechol-O-methyltransferase and brain-derived neurotrophic factor genes may interact with psychosocial stress in the development of psychosis; however, extensive further investigations are required to confirm this.

Premorbid adjustment predictors of cognitive dysfunction in schizophrenia.

Premorbid adjustment (PA) in academic and social domain is a key-predictor of cognitive performance in schizophrenia. Prior studies provided inconsistent findings regarding the differential relationships of PA domains with post-illness cognition. Multivariate associations of academic and social PA in each developmental stage (childhood, early and late adolescence) with post-onset cognitive variables were explored. Furthermore, possible differential relationships of PA domain deterioration courses with post-onset cognitive dysfunction were investigated. Seventy-five schizophrenia patients were evaluated with Premorbid Adjustment Scale (PAS). General cognitive ability, verbal IQ, verbal memory and learning, processing speed, working memory, executive function and premorbid IQ were assessed. Canonical Correlation Analyses revealed that poorer academic PA across childhood and early adolescence was related to worse post-onset verbal IQ, working memory, verbal learning and executive function, while academic PA deterioration between early and late adolescence was associated with poorer verbal learning and executive function and, as further analysis indicated, predicts IQ decline. Academic PA was exclusively associated with post-onset cognitive impairment. New evidence emerged for the specificity of each developmental period in constructing academic PA in its relation to post-illness cognition. Early premorbid academic maladjustment possibly constitutes the onset of a cognitive dysmaturational process which results to post-diagnosis impaired cognition.

Stress-Dependent Association Between Polygenic Risk for Schizophrenia and Schizotypal Traits in Young Army Recruits.

Schizotypal personality traits may increase proneness to psychosis and likely index familial vulnerability to schizophrenia (SZ), implying shared genetic determinants with SZ. Here, we sought to investigate the contribution of common genetic risk variation for SZ on self-reported schizotypy in 2 ethnically homogeneous cohorts of healthy young males during compulsory military service, enrolled in the Athens Study of Proneness and Incidence of Schizophrenia (ASPIS, N = 875) and the Learning on Genetics of Schizophrenia Spectrum study (LOGOS, N = 690). A follow-up psychometric assessment was performed in a sub-sample of the ASPIS (N = 121), 18 months later at military service completion. Polygenic risk scores (PRS) for SZ were derived based on genome-wide association meta-analysis results from the Psychiatric Genomics Consortium. In the ASPIS, higher PRSSZ significantly associated with lower levels of positive (ie, perceptual distortions), disorganization and paranoid facets of schizotypy, whereas no association with negative (ie, interpersonal) facets was noted. Importantly, longitudinal data analysis in the ASPIS subsample revealed that PRSSZ was inversely associated with positive schizotypy at military induction (stressed condition) but not at follow-up (nonstressed condition), providing evidence for environmental rather than SZ-implicated genetic influences. Moreover, consistent with prior reports, PRSSZ was positively correlated with trait anxiety in the LOGOS and additionally the recruits with higher PRSSZ and trait anxiety exhibited attenuated paranoid ideation. Together, these findings do not support an etiological link between increased polygenic liability for SZ and schizotypy, suggesting that psychosocial stress or trait anxiety may impact schizotypal phenotypic expressions among healthy young adults not genetically predisposed to SZ.

Effect of schizotypy on cognitive performance and its tuning by COMT val158 met genotype variations in a large population of young men.

BACKGROUND: Mirroring schizophrenia, specific dimensions of schizotypy are related to cognitive dysfunction. The relation of schizotypy and state psychopathology to cognitive performance and its link to catechol-O-methyltransferase (COMT) val(158) met genotype variations was studied in a large sample of young men. METHODS: State psychopathology and schizotypy were assessed with self-rated questionnaires. Cognitive performance was assessed with tests of reasoning ability, sustained attention, and verbal and spatial working memory. Subjects were genotyped for the val(158) met polymorphism of the gene for COMT (low enzymatic activity met/met, intermediate met/val, and high val/val). RESULTS: The val/val group had higher scores in measures of state psychopathology as well as negative and disorganized schizotypy dimensions, whereas there was no effect of COMT genotype on cognitive performance measures. Structural equation modeling showed that cognitive performance accuracy but not speed decreased with increasing negative schizotypy, increased with increasing paranoid schizotypy, and was not affected by state psychopathology. Increasing val loading resulted in a dose-dependent increase in the factor loading for the relation between negative schizotypy and cognitive performance accuracy. CONCLUSIONS: Different schizotypal phenotypes had opposing relations to cognitive performance in the population. COMT genotype modulated the relation between the negative schizotypal phenotype and cognitive performance.

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.

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.

Effect of COMT Val158Met polymorphism on the Continuous Performance Test, Identical Pairs Version: tuning rather than improving performance.

OBJECTIVE: It has been suggested that variation in catechol O-methyltransferase (COMT) activity associated with variation in COMT Val158Met genotypes may result in enhanced or reduced cognitive performance, depending on whether the phenotype requires cognitive stability or cognitive flexibility. The authors' goal was to determine whether, in confirmation of this prediction, performance on a measure of cognitive stability would be associated with Met loading. METHOD: COMT genotyping was investigated in relation to a measure of reaction time variability on the Continuous Performance Test, Identical Pairs Version, in a large and representative sample of 527 young men (mean age=21 years). RESULTS: Met loading was associated with reduced reaction time variability. CONCLUSIONS: Met genotype loading may confer enhanced "tuning" or greater stability in performance, possibly by stabilizing active neural representations in the prefrontal cortex during tasks involving working memory.

Neuroticism, social network, stressful life events: association with mood disorders, depressive symptoms and suicidal ideation in a community sample of women.

According to the stress-diathesis hypothesis, depression and suicidal behavior may be precipitated by psychosocial stressors in vulnerable individuals. However, risk factors for mental health are often gender-specific. In the present study, we evaluated common risk factors for female depression in association with depressive symptoms and suicidal ideation in a community sample of women. The sample was composed by 415 women evaluated for mood disorders (MDs), depressive symptoms and suicidal ideation by structured interviews and the Beck depression inventory II (BDI II). All women also filled in the Eysenck personality questionnaire to evaluate neuroticism and were interviewed for social contact frequency and stressful life events (SLEs). In the whole sample, 19% of the women satisfied criteria for MD and suicidal ideation was reported by 12% of the women. Though stressful life events, especially personal and interpersonal problems, and poor social network were associated with all the outcome variables (mood disorder, depressive symptomatology and suicidal ideation), neuroticism survived to all multivariate analyses. Social network, together with neuroticism, also showed strong association with depressive severity, independently from current depressive state. Though we were unable to compare women and men, data obtained from the present study suggest that in women neurotic traits are strongly related to depression and suicidal ideation, and potentially mediate reporting of stressful life events and impaired social network. Independently from a current diagnosis of depression, impaired social network increases depressive symptoms in the women.

Variation in catechol-o-methyltransferase val158 met genotype associated with schizotypy but not cognition: a population study in 543 young men.

BACKGROUND: Increased catechol-O-methyltransferase activity associated with variation in catechol-O-methyltransferase valine158 methionine genotypes may result in reduced dopamine neurotransmission in the prefrontal cortex and thus contribute to the poor performance of frontally mediated cognitive tasks and the occurrence of associated negative symptoms observed in patients with schizophrenia; however, reported associations between catechol-O-methyltransferase valine158 methionine genotypes and measures of cognition have not been consistent. METHODS: Catechol-O-methyltransferase genotyping, measures of schizotypy, cognitive measures of memory and attention, as well as the antisaccade eye movement task, a measure sensitive to prefrontal cortical function, were obtained in a sample of 543 young men representative for that age group (mean age 21 years). RESULTS: None of the cognitive measures was associated with catechol-O-methyltransferase valine158 methionine genotypes; however, there was an effect of high-activity allele loading on schizotypy, in particular the negative and disorganization dimensions. CONCLUSIONS: Previously reported inconsistencies in the relationship between catechol-O-methyltransferase valine158 methionine genotypes and cognition were not resolved; however, catechol-O-methyltransferase genotype may affect expression of negative schizotypy by direct or indirect effects on central dopamine neurotransmitter signaling.