Multi-omics co-localization with genome-wide association studies reveals context-specific mechanisms of asthma risk variants

Genome-wide association studies (GWASs) have identified thousands of variants associated with asthma and other complex diseases. However, the functional effects of most of these variants are unknown. Moreover, GWASs do not provide context-specific information on cell types or environmental factors that affect specific disease risks and outcomes. To address these limitations, we used cultured upper airway (sinonasal) epithelial cell models to assess transcriptional and epigenetic responses to a virus (rhinovirus [RV]) and a bacterium (Staphylococcus aureus [SA]) and provide context-specific functional annotations to variants discovered in GWASs of asthma. Using genome-wide genetic, gene expression, and DNA methylation data in RV-, SA- and vehicle-treated cells from 115 individuals, we mapped cis expression and methylation quantitative trait loci (cis-eQTLs and cis-meQTLs, respectively) in each condition. Co-localization analyses of these airway epithelial cell molecular QTLs with asthma GWAS variants revealed potential molecular disease mechanisms of asthma for GWAS variants, including QTLs at the TLSP locus that were common both to exposure conditions and childhood onset and adult onset asthma and at the 17q12-21 asthma locus that were specific to both RV exposure and childhood onset asthma, consistent with clinical and epidemiological studies of these loci. Overall, our study provides information on functional effects of asthma risk variants in airway epithelial cells and provides insight into disease-relevant microbial exposures that modulate genetic effects on transcriptional and epigenetic responses in cells and on risk for asthma in GWAS.