Dimitrios Avramopoulos

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.

Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele.

The gene for COMT is located on chromosome 22q11, an area that has been implicated in the pathogenesis of schizophrenia through linkage studies and through the detection of deletions in schizophrenics and velocardiofacial syndrome patients that often present psychotic symptomatology. Additionally catechol-O-methyl transferase activity has been found increased in schizophrenia and a functional polymorphism in the COMT gene itself has been associated with the disease, as well as with aggression in patients. We tested the hypothesis that COMT genotype for the functional Val158Met might contribute to the variance of self reported schizotypy and aggression scores in the normal population. We genotyped 379 healthy 18- to 24-year-old male individuals who had completed the PAS, SPQ and AQ questionnaires. Our results showed that self-reported schizotypy scores in both questionnaires were significantly related to COMT genotype (P = 0.028 for the PAS and P = 0.015 for the SPQ) with individuals homozygous for the high activity allele showing the highest scores. No significant differences were detected for AQ scores. We conclude that the COMT genotype for the functional Val158Met polymorphism is correlated to self-reported schizotypy in healthy males. This finding is in the same direction as reported findings on schizophrenia and it adds to the list of evidence that COMT or a nearby gene in linkage disequilibrium is involved in the pathogenesis of the disease.

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.

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.

COMT Val158Met moderation of stress-induced psychosis

BACKGROUND Exposure to stressful life events increases the risk of developing a psychotic disorder. Moreover, increased reactivity to stress seems to represent part of the vulnerability for psychosis. This study aimed to investigate whether a functional polymorphism in the catechol-O-methyltransferase (COMT Val(158)Met) gene moderates the psychosis-inducing effects of stress. METHOD A semi-experimental stress exposure paradigm was used in a sample of 306 genotyped young men (aged 19-24 years), in whom measures of psychotic symptoms were obtained at recruitment in the Greek army (exposed condition) and again after 18 months of military training (unexposed condition). RESULTS Stress exposure at army induction was associated with an increased level of psychotic symptoms. In addition, carriers of the COMT Val(158)Met Val allele were more susceptible to the effect of stress on the psychosis outcome than those with the Met/Met genotype (test for interaction: chi2 = 5.02, df = 1, p = 0.025). CONCLUSION The COMT Val(158)Met genotype may moderate the effect of stress on psychotic symptoms.

Antisaccade performance of 1,273 men: Effects of schizotypy, anxiety, and depression

A total of 1,273 conscripts of the Greek Air Force performed antisaccades and completed self-reporting questionnaires measuring schizotypy and current state-dependent psychopathology. Only 1.0% of variability in antisaccade performance indices was related to psychometric scores in the population and could be attributed more to current state-dependent symptoms such as anxiety rather than to schizotypy. In contrast, a specific increase of error rate and response latency variability and a high correlation of these 2 variables was observed in a group with very high schizotypy scores. This effect was independent of anxiety and depression, suggesting that a specific group of psychosis-prone individuals has a characteristic deviance in antisaccade performance that is not present in the general population.

Association between the GABAA receptor α5 subunit gene locus (GABRA5) and bipolar affective disorder

Genetic factors seem to play an important role in the pathogenesis of affective disorder. The candidate gene strategies are being used, among others, to identify the genes conferring vulnerability to the disease. The genes coding for the receptors of gamma-aminobutyric acid (GABA) have been proposed as candidates for affective disorder, since the GABA neurotransmitter system has been implicated in the pathogenesis of the illness. We examined the possible genetic association between the GABAA receptor α5 subunit gene locus (GABRA5) on chromosome 15 and affective disorder, in 48 bipolar patients (BP), 40 unipolar patients (UP), and 50 healthy individuals, age- and sex-matched to the patients. All patients and controls were unrelated Greeks. Diagnoses were made after direct interviews according to the DSM-IV and ICD-10 criteria. For the genotyping, a dinucleotide (CA) repeat marker was used. The polymerase chain reaction (PCR) products found were nine alleles with lengths between 272 and 290 base pairs (bp). The distribution of allelic frequencies of the GABRA5 locus differed significantly between BP patients and controls with the 282-bp allele found to be associated with BP affective disorder, while no such difference was observed between the groups of UP patients and controls nor between the two patient groups. The presence or absence of the 282-bp allele in the genotype of BP patients was not shown to influence the age of onset and the overall clinical severity, but was found to be associated with a preponderance of manic over depressive episodes in the course of the illness. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:73–80, 1998.

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.

Is the excess risk of psychosis-like experiences in urban areas attributable to altered cognitive development?

Abstract.Background:Rates of psychotic disorder and related attenuated psychotic experiences are higher in urban areas. We examined to what degree differences between urban and rural areas could be attributed to differences in cognitive development.Method:Scores on the nine subscales of the schizotypal personality questionnaire (SPQ) as well as IQ and specific neuropsychological functions of memory and attention were assessed in a representative sample of 943 young army conscripts from the 49 counties of Greece.Results:Young men from urban areas had higher scores on the SPQ subscale Odd beliefs/magical thinking (OR = 1.99, 95% CI: 1.42, 2.78), but lower scores on Excessive social anxiety (OR = 0.63, 95 % CI: 0.49, 0.81) and No close friends (OR = 0.42, 95% CI: 0.29, 0.62). Adjustment for demographic factors, IQ and specific neuropsychological functions did not change the results. When the lower scores on Excessive social anxiety and No close friends were taken into account, the differences on the Odd beliefs/magical thinking subscale became even more pronounced (OR = 2.33, 95% CI: 1.56, 3.49).Conclusions:Young men from urban areas are socially more competent, but display higher levels of positive psychotic experiences, which are not mediated by lower IQ or higher levels of neuropsychological impairment.