This R21 application proposes to use a large cohort of schizophrenia and healthy control subjects (2415 subjects) from the GENUS Consortium to clarify morphometric and genetic aspects of the corpus callosum (CC) and the lateral ventricles (LV) in schizophrenia (SZ). Our preliminary data indicate that LV and CC volume abnormalities are correlated in SZ, and index global functioning. Although abnormalities of LV and CC are hallmark of SZ and appear together in neurodevelopmental syndromes, LV and CC have rarely been studied together in SZ. Genetically, LV and CC are highly correlated, nonetheless the specific genetic determinants of this relationship are currently unknown. Recently, the SZ associated genetic risk variant miR137 has been shown to associate with LV and whole brain diffusion abnormalities in SZ where the two measures correlate. MiR137 has also been associated with poor cognitive and high negative symptoms load SZ, characterized by poor global functioning. By employing the unprecedented power of the GENUS cohort we will be able to clarify what appears to be a convergence of neuroimaging, symptomatology, cognitive measures and genetics information of LV and CC, and their relationship in one single large population of SZ and HC. This study is expected to provide novel data on the junction between morphometric measures of the corpus callosum and the lateral ventricles, their genetic background and their relation with symptoms and cognition in SZ and to identify subgroups of SZ based on these variables. The long term ramification of this proposal is the identification of novel therapeutic targets, based on miR137. T herapeutics based on miRNA, like miR137, are already been used in phase I cancer clinical trials, a disease that like SZ is polygenic. Finally, our study will reveal new information on the genetics of SZ and its relationship to symptomatology and brain variables.
The lateral ventricles and corpus callosum are genetically correlated, and are often abnormal in schizophrenia, nonetheless, the genetic determinants of their relationship in schizophrenia remains unknown. Accordingly, we will employ the largest known population of schizophrenia and healthy subjects available, which includes morphometric, functional, cognitive and genetic data (2514 subjects), where we will analyze abnormalities of the lateral ventricles and the corpus callosum, and their relationship in schizophrenia. Volumetric and diffusion data will be explored for association with one of the strongest SZ associated genetic risk variant, MIR137, and with other genes, also SZ associated and themselves regulated by MIR137 and the outcome will be the identification of schizophrenia subgroups for more targeted intervention.
