Genetic risk for schizophrenia and brain activation during the Penn Conditional Exclusion Test: A multiplex extended pedigree study.

Individuals with schizophrenia have poorer performance and often differing patterns of brain activation compared to controls on a variety of cognitive tasks, including those that require inhibition of responses and shifting to new responses. This study sought to examine the degree to which performance on a task developed to measure cognitive flexibility, the Penn Conditional Exclusion Test (PCET), and its related brain activation, as assessed on functional magnetic resonance imaging, may reflect schizophrenia genetic risk using an extended pedigree design. A total of 455 participants (27 schizophrenia probands, 170 of their first- to fourth-degree relatives, and 258 unrelated controls) completed similar versions of the PCET, both outside and inside a magnetic resonance imaging scanner. To examine brain activation that may underlie performance, ten regions of interest were identified where activation was significantly correlated with performance. To examine diagnostic specificity, we also investigated genetic correlations between diagnosed major depression and PCET performance and brain activation. Performance was significantly genetically correlated with schizophrenia both out of (R_g = -0.49, p < .001) and in the scanner (R_g = -0.59, p < .001) after false discovery rate correction. In contrast, none of the genetic correlations between schizophrenia and brain activation in the identified regions of interest were significant after false discovery rate correction. Neither behavioral performance nor brain activation measures were significantly genetically correlated with depression. These results suggest that behavioral performance on the PCET is more sensitive (and also specific compared with depression) to schizophrenia genetic risk than is functional magnetic resonance imaging activation that is correlated with performance. (PsycInfo Database Record (c) 2025 APA, all rights reserved).