Schizophrenia, inflammation and temporal change in brain morphology: an omnigenic Mendelian randomization study

The last decades of research in schizophrenia witnessed a shift of etiological speculation from neurotransmitters to inflammation. However, identifying definite inflammatory effectors of schizophrenia remains elusive due to confounding factors such as medication and metabolic status. To tackle this issue, we carried out omnigenic-based Mendelian randomization (MR) analysis to explore the inflammatory responses of schizophrenia and the brain morphological consequences caused by these SCZ-triggering inflammation responses. Our results identified seven SCZ-triggering inflammation markers, with P values surviving the Bonferroni multiple comparisons (B_NGF, P = 1.45 x 10-8; GROA (CXCL1) P = 1.15 x 10-4; IL8, P = 3.64 x 10-7; MCSF, P = 9.30 x 10-4; MCP3 (CCL7), P = 1.3 x 10-6; TNF_{beta}, P = 3.63 x 10-4; CRP, P = 1.71 x 10-32). Further, three of them, GROA (CXCL1), IL8 and CRP, could lead to significant linear change rate of brain morphologies, especially white matter in both cerebral and cerebellum. Our study is the first to use an omnigenic conceptual framework to capture the immune pathology of schizophrenia. Although future studies adopting a different methodology are needed to validate our results, our study provides another piece of evidence that extensive and low-grade neuroinflammation exists in schizophrenia and that some of these inflammation markers could be potential targets for the precise diagnosis and treatment of schizophrenia.