Variants at the MHC Region Associate With Susceptibility to Clostridioides difficile Infection: A Genome-Wide Association Study Using Comprehensive Electronic Health Records

is a major cause of healthcare-associated and community-acquired diarrhea. Host genetic susceptibility to infection has not been studied on a large-scale. A total of 1,160 infection cases and 15,304 controls were identified by applying the eMERGE infection algorithm to electronic health record data. A genome-wide association study was performed using a linear mixed model, adjusted for significant covariates in the full dataset and the antibiotic subgroup. Colocalization and MetaXcan were performed to identify potential target genes in infection - relevant tissue types. No significant genome-wide association was found in the meta-analyses of the full infection dataset. One genome-wide significant variant, rs114751021, was identified (OR = 2.42; 95%CI = 1.84-3.11; p=4.50 x 10 ) at the major histocompatibility complex region associated with infection in the antibiotic group. Colocalization and MetaXcan identified , , and as potential target genes. Down-regulation of , upregulation of and was associated with a higher risk for infection. Leveraging the EHR and genetic data, genome-wide association, and fine-mapping techniques, this study identified variants and genes associated with infection, provided insights into host immune mechanisms, and described the potential for novel treatment strategies for infection. Future replication and functional validation are needed.