Nicholas C. Stefanis

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.

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.

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.

Smooth pursuit eye movements in 1,087 men: effects of schizotypy, anxiety, and depression.

Individuals with schizotypal personality disorder or high scores in questionnaires measuring schizotypy are at high risk for the development of schizophrenia and they also share some of the same phenotypic characteristics such as eye-tracking dysfunction (ETD). The question arises whether these individuals form a distinct high-risk group in the general population or whether schizotypy and ETD co-vary in the general population with no distinct cutoff point for a high-risk group. A large sample of military conscripts aged 18–25 were screened using oculomotor, cognitive and psychometric tools for the purposes of a prospective study on predisposing factors for the development of psychosis. Schizotypy measured using the perceptual aberration scale (PAS) and the schizotypal personality questionnaire (SPQ), anxiety and depression, measured using the Symptom Checklist 90-R, had no effect on pursuit performance in the total sample. Small groups of individuals with very high scores in schizotypy questionnaires were then identified. These groups were not mutually exclusive. The high PAS group had higher root-mean-square error scores (a quantitative measure for pursuit quality) than the total sample, and the high disorganized factor of SPQ group had lower gain and higher saccade frequencies in pursuit than the total sample. The presence of significant differences in pursuit performance only for predefined high schizotypy groups favors the hypothesis that individuals with high schizotypy might present one or more high-risk groups, distinct from the general population, that are prone to ETD as that observed in schizophrenia.

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.

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.

Variation in Psychosis Gene ZNF804A Is Associated With a Refined Schizotypy Phenotype but Not Neurocognitive Performance in a Large Young Male Population

Genetic variability within the ZNF804A gene has been recently found to be associated with schizophrenia and bipolar disorder, although the pathways by which this gene may confer risk remain largely unknown. We set out to investigate whether common ZNF804A variants affect psychosis-related intermediate phenotypes such as cognitive performance dependent on prefrontal and frontotemporal brain function, schizotypal traits, and attenuated psychotic experiences in a large young male population. Association analyses were performed using all 4 available self-rated schizotypy questionnaires and cognitive data retrospectively drawn from the Athens Study of Psychosis Proneness and Incidence of Schizophrenia (ASPIS). DNA samples from 1507 healthy young men undergoing induction to military training were genotyped for 4 previously studied polymorphic markers in the ZNF804A gene locus. Single-marker analysis revealed significant associations between 2 recently identified candidate schizophrenia susceptibility variants (rs1344706 and rs7597593) and a refined positive schizotypy phenotype characterized primarily by self-rated paranoia/ideas of reference. Nominal associations were noted with all positive, but not negative, schizotypy related factors. ZNF804A genotype effect on paranoia was confirmed at the haplotype level. No significant associations were noted with central indexes of sustained attention or working memory performance. In this study, ZNF804A variation was associated with a population-based self-rated schizotypy phenotype previously suggested to preferentially reflect genetic liability to psychosis and defined by a tendency to misinterpret otherwise neutral social cues and perceptual experiences in one’s immediate environment, as personally relevant and significant information. This suggests a novel route by which schizophrenia-implicated ZNF804A genetic variation may confer risk to clinical psychosis at the general population level.

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.