Multi-Ancestry Epigenome-Wide Meta-Analysis Identifies Novel Bulk and Cell-Type-Specific Epigenetic Markers of Asthma with Severe Exacerbations
Perez-Garcia, J.; Martin-Gonzalez, E.; Chen, Z. J.; Martin-Almeida, M.; Witonsky, J.; Gorla, A.; Eng, C.; Lorenzo-Diaz, F.; Bozack, A. K.; Elhawary, J.; Hu, D.; Huntsman, S.; Gonzalez-Perez, R.; Hernandez-Perez, J. M.; Poza-Guedes, P.; Mederos-Luis, E.; Sanchez-Machin, I.; Rodriguez-Santana, J.; Villar, J.; Rifas-Shiman, S. L.; Hivert, M.-F.; Oken, E.; Gold, D. R.; Ziv, E.; Rahmani, E.; Gonzalez Burchard, E.; Cardenas, A.; Pino-Yanes, M.
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Background: Extreme-phenotype comparisons allowed the discovery of novel asthma genetic risk loci. However, this approach remains unexplored in epigenome-wide association studies (EWAS). We aimed to identify bulk and cell-specific methylation markers of asthma with severe exacerbations across diverse ancestry groups. Methods: We conducted a meta-EWAS of 739,543 CpGs in whole blood among 1,192 African American and Latino pediatric populations, comparing non-asthmatics and asthma exacerbators. Genome-wide CpGs were followed up for replication in a meta-analysis across 1,516 ethnically diverse participants and in a cross-tissue evaluation of 393 nasal samples. We conducted differentially methylated region (DMRs), cell-type-deconvoluted, and quantitative trait loci analyses (whole-genome sequencing n=1,668; RNA-seq n=1,209). We examined enrichment in traits, pathways, and druggable genes, and analyzed DNAm predictors of plasma proteins and aging. Results: DNAm at 505 CpGs and 119 DMRs in whole blood were associated with asthma exacerbations (p<9x10-8, {lambda}=1.05). We replicated 25 CpGs in blood cells, cross-validated 7 in nasal samples, and detected 42 cell-specific DNAm markers mainly driven by T cells. DNAm at 134 CpGs was associated with gene expression in whole blood, including 118 associations with T-cell receptor genes, and 446 CpGs were regulated by [≥]1 genetic variant. We found enrichment for previous associations with environmental exposures, immune disorders, immune and inflammatory pathways, and druggable genes by developmental drugs. 21 methylation-predicted plasma proteins, involved in host defense, and one lung aging clock were associated with asthma exacerbations. Conclusions: The first meta-EWAS of extreme asthma phenotypes identified hundreds of novel DNAm markers, suggesting novel methylation biomarkers and candidate drugs for asthma and supporting the role of T cells.
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