Widespread, heritable, brain alterations in individuals with schizophrenia and individuals 'at risk': Evidence for a cortical thickness intermediate phenotype

Background: Studies investigating cortical thickness in schizophrenia using genetically sensitive samples are scarce and it remains unclear to what extent heritable factors are involved in cortical thickness alterations that have been found in schizophrenia. In the present family study, we examined whether there was evidence for i)an intermediate cortical thickness phenotype in schizophrenia and for ii) heritability of cortical thickness alterations. Methods: T1-weighted MRI scans were acquired on a 3 Tesla scanner from 89 patients with schizophrenia, 98 healthy siblings at higher than average genetic risk for schizophrenia and 87 controls. Free surfer was used to measure cortical thickness. Differences between study groups were assessed, after the data was transformed into a hierarchical structure consisting of 68 predefined regions of interest (ROI) per subject. The statistical interaction between risk for schizophrenia (group status) and brain region on cortical thickness was assessed with multilevel regression analyses. Heritability was examined by calculating the Risch λ.Results: There was a significant group x ROI interaction, in the model of cortical thickness, for patients compared to controls (χ2=14100,P=0.00) and siblings compared to controls (χ2=12828, P=0.00),indicating that the effect of group status on cortical thickness varied with brain region. Patients and siblings had significant thinning of the cortex in frontal, parietal and temporal regions, compared to controls. Patients and sblings also showed some increases in cortical thickness in cingulate, frontal and temporal regions. In addition, there were patient-specific cortical thicknesss alterations. The Risch λ heritability values were high in several regions spread over the brain, predominantly in frontal and temporal cortices. All regions with similar patterns of cortical thickness alterations in patients and siblings showed high heritability values. Discussion: Beside patient-specific cortical thickness alterations, the results revealed heritable, globally distributed cortical thickness reductions and, to a lesser extent increases, in psychotic patients and their siblings. There was evidence for a cortical thickness intermediate phenotype in frontal, parietal, temporal and cingulate regions.