Substantial genetic link between IQ and working memory: implications for molecular genetic studies on schizophrenia. the European twin study of schizophrenia (EUTwinsS).

While evidence is accumulating to support specific neurocognitive deficits as putative endophenotypes for schizophrenia, the heritability of these deficits in healthy subjects and whether they share common genetic influences, is not well established. In the present study, 529 healthy adult twins from two centers within the European Twin Study Network on Schizophrenia (EUTwinsS) were assessed on two domains that are consistently found to be particularly compromised in schizophrenia. Specifically, Intellectual Quotient Score (IQ) and the Letter-Number Sequencing Test (LNS), a measure of working memory, were measured in all twins. Latent variable components were explored through structural equation modeling, and common genetic underpinnings were examined using bivariate analyses. Results showed that the phenotypic correlation between IQ and working memory was almost entirely attributed to shared genetic variance (95.5%). We discuss the potential use of a combined measure of IQ and working memory to improve the power of molecular studies in detecting the genetic mechanisms underlying schizophrenia.

Prefrontal deviations in function but not volume are putative endophenotypes for schizophrenia.

This study sought to systematically investigate whether prefrontal cortex grey matter volume reductions are valid endophenotypes for schizophrenia, specifically investigating their presence in unaffected relatives, heritability, genetic overlap with the disorder itself and finally to contrast their performance on these criteria with putative neuropsychological indices of prefrontal functioning. We used a combined twin and family design and examined four prefrontal cortical regions of interest. Superior and inferior regions were significantly smaller in patients. However, the volumes of these same regions were normal in unaffected relatives and therefore, we could confirm that such deficits were not due to familial effects. Volumes of the prefrontal and orbital cortices were, however, moderately heritable, but neither shared a genetic overlap with schizophrenia. Total prefrontal cortical volume reductions shared a significant unique environmental overlap with the disorder, suggesting that the reductions were not familial. In contrast, prefrontal (executive) functioning deficits were present in the unaffected relatives, were moderately heritable and shared a substantial genetic overlap with liability to schizophrenia. These results suggest that the well recognized prefrontal volume reductions are not related to the same familial influences that increase schizophrenia liability and instead may be attributable to illness related biological changes or indeed confounded by illness trajectory, chronicity, medication or substance abuse, or in fact a combination of some or all of them.

Genetic overlap between schizophrenia and selective components of executive function.

Impairments in selective components of executive function are seen in unaffected family members of patients with schizophrenia and may represent the biological expression of increased genetic risk. However no study has quantified the extent to which liability to schizophrenia overlaps genetically with that of executive dysfunction. We studied a total of 418 monozygotic and dizygotic twins, including pairs concordant and discordant for schizophrenia. Participants completed the trail making test part A and verbal fluency tasks to assess initiation, TMT part B to test mental flexibility, and the WAIS-III to assess general intellectual function. Bivariate genetic modeling was used to investigate whether selective measures of executive processing are genetically linked to schizophrenia and to quantify the genetic (i.e. heritability) and environmental contributions to their variability. Genetic influences contributed substantially to test variance for initiation and mental flexibility. Genetic factors were the main source of the phenotypic correlations between schizophrenia and these processes. Verbal fluency tasks shared a large genetic correlation with IQ whilst TMT scales did not, suggesting that they measure discreet processes, and therefore indexing discreet endophenotypes. Both verbal fluency and mental flexibility meet some of the criteria for endophenotypes, but our data suggest that mental flexibility is a purer cognitive process sharing very little common variance with general intellectual functioning. The inclusion of this mental flexibility phenotype in linkage or association analysis should improve the power to detect susceptibility genes for schizophrenia.