Genetic and Environmental Influences on Brain Function In Schizophrenia. An FMRI Study of the Maudsley Twin and Family Cohorts

Abstract

BACKGROUND: Schizophrenia is a heritable but aetiologically complex disorder. Intermediate phenotypes as quantitative traits pathophysiologically closer to the underlying genetic risks represent an experimental strategy to help address this complexity. Verbal fluency performance satisfies many criteria for an intermediate phenotype for schizophrenia. Our aim was to assess the influence of genetic and environmental factors on this executive function task in schizophrenia. METHODS: We used a twin-sibling study of 206 subjects; 163 twins, varying in their zygosity and concordance for schizophrenia, and 43 singletons from siblings varying in their concordance for schizophrenia. We assessed performance and regional brain activation using functional magnetic resonance imaging, during a phonological verbal fluency task. After between group testing, we conducted full genetic modelling. RESULTS: Across groups there was a differential pattern of activation in fronto-temporal areas. Patients and their unaffected relatives developed greater activation in the left inferior frontal gyrus, and greater deactivation in the left hippocampal and middle temporal gyri bilaterally. These features were maximally evident in subjects with schizophrenia, and least in controls. When the analysis was restricted to the unaffected relatives and healthy controls, a similar pattern was evident, with the unaffected relatives showing greater inferior frontal and left superior temporal activation, and greater right parahippocampal and right superior/middle temporal deactivation than healthy controls. Genetic modelling indicated a phenotypic correlation between schizophrenia and increased activity in the inferior frontal gyrus and reduced activity in the left middle temporal gyrus and left hippocampus, which was principally due to shared genetic effects. DISCUSSION: Both schizophrenia and its familial vulnerability were associated altered frontal, parahippocampal and temporal activation during verbal fluency. The altered left inferior frontal activity was particularly associated with schizophrenia, while altered right middle/superior temporal and right medial temporal activity were more heritable and more intimately linked to the genetic risk for schizophrenia.