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The Trans-National Asthma Genetic Consortium (TAGC) identified 878 SNPs associated with asthma through a large meta-analysis of GWAS. To date, the mechanisms underlying these associations are largely unknown. We hypothesized that "TAGC SNPs" affect asthma risk by altering gene expression in airway epithelium, either directly or through DNA methylation. We examined methylation and expression in nasal epithelium, which are highly correlated with those in bronchial epithelium. Methods: Cross-sectional study of Puerto Rican children and adolescents (aged 9 to 20 years) with (n=228) and without (n=241) asthma. We assessed genome-wide genotypes (using the HumanOmni2.5 BeadChip platform, Illumina), and genome-wide DNA methylation (using the HumanMethylation450 BeadChip, Illumina) and RNA sequencing (using the Illumina NextSeq 500 platform) in nasal epithelium from study participants, as previously described (Forno et al, 2019). We conducted an expression quantitative trait loci (eQTL) analysis to identify direct associations between 869 TAGC SNPs and expression levels of cis-genes (within 1 Mb), and Sobel mediation analyses to identify indirection associations between the SNPs and gene expression through methylation in nasal epithelium, Moreover, we tested whether genes whose expression in nasal (airway) epithelium are associated with TAGC SNPs are also differentially expressed (DE) in atopic asthma. Results: We identified 1,150 direct associations between the TAGC SNPs and cis-expression of genes. Most of these SNPs regulated distant cis-genes (average distance= ∼200 kb) (Figure 1B). The mediation analysis further showed that 4,571 (89.2%) of 5,119 (direct and indirect) SNP-gene expression associations were mediated by DNA methylation. Of 114 genes whose expression was associated with TAGC SNPs, 54 were DE in atopic asthma, including novel genes and known asthma-susceptibility genes. Data were publicly available for 50 of these DE genes in a cohort of 72 African American children, in whom 21 (42%) were also DE by atopic asthma. Conclusions: Many TAGC SNPs regulate expression of distant cis-genes (i.e. genes that were not adjacent to or containing the SNPs). Most SNP-gene expression associations are mediated by DNA methylation, supporting a strong regulatory role of methylation on gene expression in airway epithelium. Nearly half of the genes whose expression in nasal airway epithelium are associated with TAGC SNPs are also associated with atopic asthma. Our findings further support a key role of DNA methylation and gene expression in airway epithelium on the pathogenesis of atopic asthma.

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