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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.

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.

Background Increased catechol- O -methyltransferase activity associated with variation in catechol- O -methyltransferase valine 158 methionine genotypesmay 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 valine 158 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 valine 158 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 valine 158 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.