A genome-wide association study of adults with community-acquired pneumonia

Abstract

ABSTRACTIntroductionCommunity-acquired pneumonia (CAP) is associated with high morbidity and hospitalization rate. In infectious diseases, host genetics plays a critical role in susceptibility and immune response, and the immune pathways involved are highly dependent on the microorganism and its route of entry.ObjectiveTo identify genetic risk loci for CAP using a one-stage genome-wide association study (GWAS).MethodsWe performed a GWAS on 3,765 Spanish individuals, including 257 adult patients hospitalized with CAP and 3,508 population controls. Pneumococcal CAP was documented in 30% of patients; the remaining 70% were selected among patients with unidentified microbiological etiology. Genotyping and imputation allowed testing the association of 7,6 million variants using logistic regressions. Subsequently, we prioritized genes and likely causal variants based on Bayesian fine mapping and functional evidence. Imputation and association testing of the classic HLA alleles and amino acids was also conducted.ResultsWe revealed six independent sentinel variants that were genome-wide significant (p<5×10−8), three located on chromosome 6p21.32, and one for each of the chromosomes 4q28.2, 11p12, and 20q11.22. Our analyses prioritizedC4orf33on 4q28.2,TAPBPon 6p21.32, andZNF341on 20q11.22. Interestingly, genetic defects ofTAPBPandZNF341are previously known inborn errors of immunity predisposing to bacterial pneumonia, including pneumococcus andHaemophyilus influenzae. Associations were all non-significant for the classic HLA alleles.ConclusionsWe completed a GWAS of CAP and identified four novel risk loci involved in CAP susceptibility.