Temporal changes in brain morphology related to inflammation and schizophrenia: an omnigenic Mendelian randomization study.

BACKGROUND

Over the past several decades, more research focuses have been made on the inflammation/immune hypothesis of schizophrenia. Building upon synaptic plasticity hypothesis, inflammation may contribute the underlying pathophysiology of schizophrenia. Yet, pinpointing the specific inflammatory agents responsible for schizophrenia remains a complex challenge, mainly due to medication and metabolic status. Multiple lines of evidence point to a wide-spread genetic association across genome underlying the phenotypic variations of schizophrenia.

METHOD

We collected the latest genome-wide association analysis (GWAS) summary data of schizophrenia, cytokines, and longitudinal change of brain. We utilized the omnigenic model which takes into account all genomic SNPs included in the GWAS of trait, instead of traditional Mendelian randomization (MR) methods. We conducted two round MR to investigate the inflammatory triggers of schizophrenia and the resulting longitudinal changes in the brain.

RESULTS

We identified seven inflammation markers linked to schizophrenia onset, which all passed the Bonferroni correction for multiple comparisons (bNGF, GROA(CXCL1), IL-8, M-CSF, MCP-3 (CCL7), TNF-

CONCLUSION

With an omnigenic approach, our study sheds light on the immune pathology of schizophrenia. Although these findings need confirmation from future studies employing different methodologies, our work provides substantial evidence that pervasive, low-level neuroinflammation may play a pivotal role in schizophrenia, potentially leading to notable longitudinal changes in brain morphology.