Key regions aberrantly connected within cerebello-thalamo-cortical circuit and their genetic mechanism in schizophrenia: an fMRI meta-analysis and transcriptome study.

Abstract

Recent studies have showed aberrant connectivity of cerebello-thalamo-cortical circuit (CTCC) in schizophrenia (SCZ), which might be a heritable trait. However, these individual studies vary greatly in their methods and findings, and important areas within CTCC and related genetic mechanism are unclear. We searched for consistent regions of circuit dysfunction using a functional magnetic resonance imaging (fMRI) meta-analysis, followed by meta-regression and functional annotation analysis. Gene annotation analysis was performed to identify genes over-expressed in these regions by using the Allen Human Brain Atlas, followed by a set of gene functional feature analyses. 19 studies (1333 patients and 1174 healthy controls) were included in this meta-analysis. SCZ was characterized by hyperconnectivity of the auditory network, visual system, and sensorimotor areas, and hypoconnectivity of the frontal gyrus, cerebellum, thalamus, and caudate nucleus, which were significantly linked to age, sex, duration of illness, and the severity of symptoms and functionally enriched in domains involving self, sensory, action, and social. 2922 genes were significantly over-expressed in these regions, which were enriched for important molecular functions, biological processes, and cellular components of the neurons/cells in the brain as well as SCZ and other mental diseases. These genes were specially expressed in the brain tissue, in the neurons of the cerebellum, subcortex and cortex and during nearly all developmental stages, and constructed a protein-protein interaction network supported by 85 hub genes with functional significance. These findings suggest key regions aberrantly connected within CTCC in SCZ, which may indicate the neural substrate of "cognitive dysmetria" and be a consequence of complex interactions from a wide range of genes with diverse functional features.