Pneumonia: host susceptibility and shared genetics with pulmonary function and other traits

Abstract

Pneumonia is a common and severe infectious lung disease. Host genetics, together with underlying medical and lifestyle conditions, determine pneumonia susceptibility. We performed a secondary analysis of the results of two genome-wide studies for pneumonia in 23andMe participants (40 600 cases/90 039 controls) (Tian et al., 2017) and UK Biobank (BB) participants (12 614 cases/324 585 controls) (via the Global Biobank Engine) and used the GTEx database to correlate the results with expression quantitative trait loci (eQTLs) data in lung and whole blood. In the 23andMe pneumonia single nucleotide polymorphism (SNP) set, 177 genotyped SNPs in the human leukocyte antigen (HLA) region satisfied the genome-wide significance level, P ≤ 5·0E-08. Several target genes (e.g. C4A, VARS2, SFTA2, HLA-C, HLA-DQA2) were unidirectionally regulated by many HLA eSNPs associated with a higher risk of pneumonia. In lung, C4A transcript was up-regulated by 291 pneumonia risk alleles spanning the half the HLA region. Among SNPs correlated with the expression levels of SFTA2 and VARS2, approximately 75% overlapped: all risk alleles were associated with VARS2 up-regulation and SFTA2 down-regulation. To find shared gene loci between pneumonia and pulmonary function (PF), we used data from the Global Biobank Engine and literature on genome-wide association studies (GWAS) of PF in general populations. Numerous gene loci overlapped between pneumonia and PF: 28·8% in the BB data set and 49·2% in the 23andMe data set. Enrichment analysis within the database of Genotypes and Phenotypes (dbGaP) and National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) Catalog of pneumonia and pneumonia/PF gene sets identified significant overlap between these gene sets and genes related to inflammatory, developmental, neuropsychiatric and cardiovascular and obesity-related traits.

Keywords: C4A; eQTLs; genetic susceptibility; pneumonia; pulmonary function.

Figure 1

Overall study design.

Figure 2

Manhattan plot for single nucleotide polymorphism (SNP) associations with pneumonia plotted according to chromosomal location (x‐axis), with −log10 P‐values (y‐axis): (a) overview for both studies, genes outside of the human leukocyte antigen (HLA) region with P < 1E‐05 are signed; (b) the HLA region, from the data of Tian and co‐authors [9], the highest results among those with P < 5E‐08 are annotated.

Figure 3

Circus Manhattan plot for pneumonia‐associated expression‐associated single nucleotide polymorphisms (eSNPs) according to the GTEx data set. (a) Circus Manhattan plot: chromosomes are ordered around the circumference; −log10 P‐values for eSNPs are indicated inside circles for lung, (a) positive normalized effect size (NES), (b) negative NES and whole blood, (c) positive NES and (d) negative NES. Data are shown for variant alleles independently of the direction of their association (risk or protective) with pneumonia. (b) Summary statistics.

Figure 4

Allele‐specific expression of pneumonia‐associated lung expression‐associated single nucleotide polymorphisms (eSNPs) in the human leukocyte antigen (HLA) region. (a) Manhattan plot for pneumonia‐associated eSNPs according to GTEx data. SNPs are plotted by chromosomal position (x‐axis) and −log10 expression P‐values (y‐axis). Up‐regulated genes by risk (red) or protective (green) alleles are shown in the upper segment; down‐regulated genes are displayed in the lower segment. Transcripts with the best P‐value for allelic bias are signed. Top five up‐ and down‐regulated genes are highlighted with red and green dots. (b) Matrix of pairwise intersections of eSNPs for the protein‐coding genes with SNP count > 10. Only SNPs that unidirectionally influenced gene expression levels were considered (if risk allele was correlated with up‐regulation, the protective allele was correlated with down‐regulation and vice or versa). Genes are set in a particular order to correspond with chromosomal location.

Figure 5

Overlapping gene loci associated with pneumonia and pulmonary function (PF). (a) Chromosome ideogram with coloured dots placed at the cytogenetic band location of genes/gene regions (one dot per locus) associated with pneumonia and PF in the data sets under study. The centromere area, highlighted in dark blue, separates the upper short ‘p’ arm and lower long ‘q’ arm. (b) Summary statistics. The term ‘overlapped region’ is applied when single nucleotide polymorphisms (SNPs) associated with pneumonia and PF were located within a 500‐kb region proximal/distal to the start/end of the same nearest up‐ and downstream genes. The term ‘partially overlapped regions’ is applied when SNPs associated with pneumonia and PF were located within a 500‐kb region of the same nearest up‐ or downstream genes.

Figure 6

Disease/trait enrichment analysis of gene sets related to pneumonia and pneumonia/pulmonary function (PF). The number of phenotypes falling into broad categories is indicated in a doughnut chart: an outer ring is related to the pneumonia gene set, while an inner ring is related to the subset of pneumonia/PF genes: (a) database of Genotypes and Phenotypes (dbGaP), UK BioBank (BB); (b) dbGaP, 23andMe; (c) National Human Genome Research Institute‐European Bioinformatics Institute (NHGRI‐EBI) genome‐wide association study (GWAS) Catalog, BB; (d) NHGRI‐EBI GWAS Catalog, 23andMe.