Genetic Susceptibility to Acute Viral Bronchiolitis

Abstract

Background: Acute viral bronchiolitis is a major cause of infant hospitalizations worldwide. Childhood bronchiolitis is considered a risk factor for asthma, suggesting shared genetic factors and biological pathways. Genetic risk loci may provide new insights into disease pathogenesis.

Methods: We conducted a genome-wide association study to examine the genetic contributions to bronchiolitis susceptibility in the FinnGen project data. We analyzed 1465 infants hospitalized for bronchiolitis who were <2 years of age and 356 404 individuals without a history of acute lower respiratory infections.

Results: The genome-wide association study identified associations (P < 5 × 10-8) for variants in gasdermin B (GSDMB) and a missense variant in cadherin-related family member 3 (CDHR3). Children with bronchiolitis in infancy were more likely to develop asthma later in life as compared with controls. The 2 associated loci were previously linked to asthma and susceptibility to wheezing illness by causative agents other than respiratory syncytial virus (RSV). The identified loci were associated with overall bronchiolitis, with larger effects in non-RSV than RSV-induced infection.

Conclusions: Our results suggest that genetic variants in CDHR3 and GSDMB modulate susceptibility to bronchiolitis, especially when caused by viruses other than RSV. Severe bronchiolitis in infancy may trigger the development of asthma in genetically susceptible individuals, or it could be a marker of genetic predisposition to asthma.

Keywords: CDHR3; GSDMB; asthma; bronchiolitis; genetic risk factors.

Figure 1.

Manhattan plot and regional association plots of the genome-wide association study of bronchiolitis. The y- and x-axes show −log₁₀  P values vs chromosomal positions of the tested variants. The dashed line denotes the threshold of genome-wide significance (P < 5 × 10⁻⁸).

Figure 2.

Effect sizes of the associated loci in the genome-wide association study of bronchiolitis and the subanalysis of RSV and non-RSV bronchiolitis. Effects are shown for the index variant in the (A) CDHR3 and (B) GSDMB loci. RSV, respiratory syncytial virus.

Figure 3.

Associations of the bronchiolitis genome-wide association study lead single-nucleotide polymorphisms among the FinnGen DF10 phenotype categories. The association P value is based on the phenotype with the strongest within-category association. The associations are capped into a −log₁₀  P value of 10.

Figure 4.

Genetic correlation between bronchiolitis and other complex traits. The figure shows the top 10 correlating traits. Bronchiolitis correlations were tested with data originating from 772 European genome-wide association studies obtained via the Integrative Epidemiology Unit’s OpenGWAS Project [37]. The reports describing the genome-wide association study data can be searched online in the OpenGWAS database (https://gwas.mrcieu.ac.uk/) with the identification numbers (GWAS_ID) provided in Supplementary Table 6.