A transcriptome-wide Mendelian randomization study in isolated human immune cells highlights interferon regulatory transcription factor 3 as a schizophrenia hub gene.

Immune mechanisms are associated with schizophrenia, although the precise mechanisms involved are not fully understood. To identify immune genes associated with schizophrenia, we conducted a transcriptome-wide Mendelian randomization study using gene expression exposures from 29 cis-eQTL datasets encompassing 11 unique immune cell types, all publicly available from the eQTL catalogue. These analyses highlighted 196 genes, including 67 located within the human leukocyte antigen (HLA) region. Enrichment analyses indicated an over-representation of immune genes, which was driven primarily by the HLA genes. Stringent validation and replication steps retained 61 candidate genes, 16 of which were immune-related. As an exemplar, we performed follow-up analyses focused on interferon regulatory transcription factor 3 (IRF3), which coordinates interferon responses to viral infections. We found evidence of shared genetic aetiology between schizophrenia and autoimmune diseases at the IRF3 locus, and a significant enrichment of IRF3 chromatin binding at schizophrenia risk loci. Together, our findings suggest the HLA region may be responsible for a wide range of immune perturbations not directly related to schizophrenia aetiology. They also provide support for IRF3 as a schizophrenia hub gene responsible for mediating the impact of viral infections on schizophrenia risk, and as a potential novel therapeutic target. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The source data were publicly available prior to the initiation of this study, and can be found at: (1) https://www.ebi.ac.uk/eqtl/Data_access/, (2) https://pgc.unc.edu/for-researchers/download-results/. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors