Prefrontal Deviations in Function but not Volume are Putative Endophenotypes for Schizophrenia

Abstract

Background: Endophenotypes are biological traits, intermediate between the genes and the clinical phenotype, that increase disease susceptibility. Aims: This study sought to systematically investigate whether prefrontal cortex grey matter volume reductions are valid endophenotypes for schizophrenia, specifically investigating a) their presence in unaffected relatives, b) their heritability c) their genetic overlap with the disorder itself, and finally d) their performance on these criteria with neuropsychological indices of prefrontal functioning. Methods: We used a combined twin and family design and examined four prefrontal cortical regions of interest (ROIs). Results: Not unexpectedly the superior and inferior regions were significantly smaller in patients. However this was not the case in the unaffected relatives so we could confirm that these deficits were not due to familial effects. Volume of the prefrontal and orbital cortices were 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 again that the reductions were not familial. By way of contrast, prefrontal (executive) functioning deficits were present in the unaffected relatives, were moderately heritable and shared a substantial genetic overlap with the disorder. Conclusions: These results suggest that the well‐recognized prefrontal volume reductions commonly found in schizophrenia could be really epiphenomena and may be attributable to or confounded by illness trajectory or duration, chronicity, medication, or substance abuse, or in fact a summation of some or all of them.