Host genetic effects in pneumonia

Abstract

Given the coronavirus disease 2019 (COVID-19) pandemic, investigations into host susceptibility to infectious diseases and downstream sequelae have never been more relevant. Pneumonia is a lung disease that can cause respiratory failure and hypoxia and is a common complication of infectious diseases, including COVID-19. Few genome-wide association studies (GWASs) of host susceptibility and severity of pneumonia have been conducted. We performed GWASs of pneumonia susceptibility and severity in the Vanderbilt University biobank (BioVU) with linked electronic health records (EHRs), including Illumina Expanded Multi-Ethnic Global Array (MEGA^EX)-genotyped European ancestry (EA, n= 69,819) and African ancestry (AA, n = 15,603) individuals. Two regions of large effect were identified: the CFTR locus in EA (rs113827944; OR = 1.84, p value = 1.2 × 10^-36) and HBB in AA (rs334 [p.Glu7Val]; OR = 1.63, p value = 3.5 × 10^-13). Mutations in these genes cause cystic fibrosis (CF) and sickle cell disease (SCD), respectively. After removing individuals diagnosed with CF and SCD, we assessed heterozygosity effects at our lead variants. Further GWASs after removing individuals with CF uncovered an additional association in R3HCC1L (rs10786398; OR = 1.22, p value = 3.5 × 10^-8), which was replicated in two independent datasets: UK Biobank (n = 459,741) and 7,985 non-overlapping BioVU subjects, who are genotyped on arrays other than MEGA^EX. This variant was also validated in GWASs of COVID-19 hospitalization and lung function. Our results highlight the importance of the host genome in infectious disease susceptibility and severity and offer crucial insight into genetic effects that could potentially influence severity of COVID-19 sequelae.

Keywords: GWAS; biobank; electronic health record; host genetic effect; pneumonia.

Figure 1

SNP associations with pneumonia in BioVU MEGA^EX-genotyped EA (A) Miami plot of pneumonia susceptibility (individual with pneumonia versus control individuals) with (top) and without (bottom) individuals diagnosed with CF. (B) Miami plot of pneumonia severity (pneumonia inpatients versus outpatients) with (top) and without (bottom) individuals diagnosed with CF.

Figure 2

SNP associations with pneumonia in BioVU MEGA^EX-genotyped AA (A) Miami plot of pneumonia susceptibility (individual with pneumonia versus control individuals) with (top) and without (bottom) individuals diagnosed with CF and SCD. (B) Miami plot of pneumonia severity (pneumonia inpatients versus outpatients) with (top) and without (bottom) individuals diagnosed with CF and SCD.

Figure 3

LocusZoom plot of R3HCC1L with the genome-wide association study results of pneumonia inpatients versus outpatients from BioVU MEGA^EX-genotyped EA excluding CF-affected individuals Linkage disequilibrium and recombination rate estimates come from 1000 Genomes Project phase 3 European superpopulation reference data.