Multi-ancestry epigenome-wide association study of asthma exacerbations

First two authors co-first. <bold>Background:</bold> Asthma exacerbations (AEs) result from the interaction of genetic and environmental factors, potentially captured by DNA methylation (DNAm). However, only one epigenome-wide association study (EWAS) of AEs has been performed in Europeans. <bold>Aim:</bold> To identify population-specific and shared DNAm markers of AEs. <bold>Methods:</bold> Blood DNAm was measured in 599 Latinos and 394 African Americans with asthma using the EPIC array (Illumina). The association of DNAm at differentially methylated positions (CpGs) and regions (DMRs) with AEs was assessed in each population separately and then meta-analysed. We explored the most significant CpGs identified in Europeans (n=406) for replication in admixed populations. Moreover, a multi-ancestry meta-EWAS was performed across admixed and European populations (n=1,399). We tested the association of exacerbation-related CpGs on gene expression. <bold>Results:</bold> The most significant CpG in admixed populations was cg21608069 (<italic>MKRN2</italic>) (logFC=0.09, <italic>p</italic>=9.56x10^-8), and 3 CpGs previously associated with AEs in Europeans were replicated (<italic>p</italic><0.05): cg15508223 (<italic>LOC100130691</italic>), cg25345365 (<italic>ZBTB16</italic>), and cg03546163 (<italic>FKBP5</italic>). The multi-ancestry meta-EWAS identified a novel association for CpG cg17148519 (<italic>USP7</italic>) (logFC=0.09; <italic>p</italic>=1.41x10^-7). A total of 19 DMRs were associated with AEs, with a DMR at the <italic>PKP3</italic> gene being the most significant in the multi-ancestry meta-analysis (<italic>p</italic>=1.3x10^-9). Finally, DNAm at CpG cg03546163 was associated with decreased <italic>FKBP5</italic> expression (logFC=-0.16; <italic>p</italic>=8.57x10^-4). <bold>Conclusions:</bold> The first EWAS of AEs in admixed populations revealed novel and shared epigenetic marks with Europeans. <bold>Grant:</bold> NIH R56MD013312, MICIU/AEI/10.13039/501100011033 (PID2020-116274RB-I00).