Abstract
There is limited data on host-specific genetic determinants of susceptibility to bacterial and viral infections. Genome-wide association studies using large population cohorts can be a first step towards identifying patients prone to infectious diseases and targets for new therapies. Genetic variants associated with clinically relevant entities of bacterial and viral infections (e.g., abdominal infections, respiratory infections, and sepsis) in 337,484 participants of the UK Biobank cohort were explored by genome-wide association analyses. Cases (n = 81,179) were identified based on ICD-10 diagnosis codes of hospital inpatient and death registries. Functional annotation was performed using gene expression (eQTL) data. Fifty-seven unique genome-wide significant loci were found, many of which are novel in the context of infectious diseases. Some of the detected genetic variants were previously reported associated with infectious, inflammatory, autoimmune, and malignant diseases or key components of the immune system (e.g., white blood cells, cytokines). Fine mapping of the HLA region revealed significant associations with HLA-DQA1, HLA-DRB1, and HLA-DRB4 locus alleles. PPP1R14A showed strong colocalization with abdominal infections and gene expression in sigmoid and transverse colon, suggesting causality. Shared significant loci across infections and non-infectious phenotypes in the UK Biobank cohort were found, suggesting associations for example between SNPs identified for abdominal infections and CRP, rheumatoid arthritis, and diabetes mellitus. We report multiple loci associated with bacterial and viral infections. A better understanding of the genetic determinants of bacterial and viral infections can be useful to identify patients at risk and in the development of new drugs.
Highlights
There is limited data on host-specific genetic determinants of susceptibility to bacterial and viral infections
In the interpretation of result, we focused on SNPs with minor allele frequency (MAF) ≥ 1% and Genome-wide association studies (GWAS) catalog hits with r2 ≥ 0.30 and distance ≤ 100 kb from the genetic variant identified in our study
human leucocyte antigen (HLA)-DQ and HLA-DR are major histocompatibility complex (MHC) class II molecules that play a key role in the adaptive immune response, especially against bacterial infections, by presenting pathogen antigens mainly to the CD4 + T helper cells[18]
Summary
There is limited data on host-specific genetic determinants of susceptibility to bacterial and viral infections. History of common infections in > 200,000 individuals identified multiple loci associated with disease, most notably in genes related to the immune r esponse[8] These results, along with studies of heritability of infectious diseases[9], suggest that genetic determinants play an important role for patient susceptibility to bacterial and viral infections. Exploring such undiscovered host-specific factors could be important for detection of patients at increased risk of infection and provide an avenue to identify targets for new drugs. We assessed the impact of genetic variation on the incidence of bacterial and viral infectious diseases in a cohort of ~ 350,000 individuals using results of genome-wide genotype data and diagnose codes from hospital inpatient and death registries
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