The role of epigenetics in the pathogenesis of asthma acquisition in adolescence and post-adolescence has been unknown. We carried out a longitudinal epigenome-wide association study, using data from the Isle of Wight Birth Cohort (IOWBC). To improve statistical power, we first screened CpGs based on associations of DNA methylation (DNAm) at an age of 10 years (pre-adolescence) with asthma acquisition at 10–18 years (during adolescence). A logistic regression with repeated measures was applied to CpGs that passed screening to examine the associations of pre-adolescence DNAm with asthma acquisition from 10–18 years and 18–26 years, with an interaction term to evaluate transition period specificity. Findings were further tested in an independent birth cohort, ALSPAC. In total, 205 CpGs (with 150 being females) showed associations with asthma acquisition (main or interaction effects) at FDR = 0.05 in IOWBC, of which 112 (90 being females) showed consistent associations in the ALSPAC. Genes that the identified CpGs were mapped to, e.g., AKAP1 and ENO1, have been shown to be associated with the risk of asthma. Our findings indicated that DNAm at specific CpGs was associated with asthma acquisition. CpGs showing such associations were likely to be different between males and females and, at certain CpGs, were unique to a specific transition period.

DNA methylation (DNAm) patterns over time at 1146 CpGs on coronavirus-related genes were assessed to understand whether the varying differences in susceptibility, symptoms, and the outcomes of the SARS-CoV-2 infection in children and young adults could be explained through epigenetic alterations in a host cell’s transcriptional apparatus to coronaviruses. DNAm data from the Isle of Wight birth cohort (IOWBC) at birth, 10, 18, and 26 years of age were included. Linear mixed models with repeated measurements stratified by sex were used to examine temporal patterns, and cluster analysis was performed to identify CpGs following similar patterns. CpGs on autosomes and sex chromosomes were analyzed separately. The association of identified CpGs and expression of their genes were evaluated. Pathway enrichment analyses of the genes was conducted at FDR = 0.05. DNAm at 635 of the 1146 CpGs on autosomes showed statistically significant time effects (FDR = 0.05). The 635 CpGs were classified into five clusters with each representing a unique temporal pattern of DNAm. Of the 29 CpGs on sex chromosomes, DNAm at seven CpGs in males and eight CpGs in females showed time effects (FDR = 0.05). Sex-specific and non-specific associations of DNAm with gene expression were found at 24 and 93 CpGs, respectively. Genes which mapped the 643 CpGs represent 460 biological processes. We suggest that the observed variability in DNAm with advancing age may partially explain differing susceptibility, disease severity, and mortality of coronavirus infections among different age groups.

The cause and underlying mechanisms that contribute to asthma pathogenesis are not well known. Both genome- and epigenome-wide association studies have identified genes associated with asthma risk. It is unknown to what extent genes identified in these two types of studies overlap. Based on existing literature and the DisGeNET database, we extracted overlapping genes identified in genetic and epigenetic studies of childhood asthma. Through analyses of variance, we assessed whether DNA methylation (DNAm) at 5′-C-phosphate-G-3′ (CpGs) on the overlapping genes was associated with neighboring single-nucleotide polymorphisms (SNPs) within 1M base pairs (bps) and with low linkage disequilibrium ( r² < 0.2) in the childhood asthma-related genes. In total, 285 genes from genetic studies and 226 genes from epigenetic studies were shown to be associated with asthma risk, of which six overlap. Of the six genes, 79 CpGs and 8229 unique neighboring SNPs (1M bps) were included in methylation quantitative loci (methQTL) assessment analyses. We tested the association of DNAm at each of the 79 CpG sites with its neighboring SNPs. After adjusting for multiple testing by controlling the false discovery rate to 0.05 when testing methQTL for each CpG site, we found statistically significant associations in three genes with their neighboring SNPs and identified 34 unique methQTLs. The rather limited overlap in genes between genetic and epigenetic studies on asthma and the absence of methQTL in some of the overlapping genes highlight a need to jointly, rather than independently, examine genetic and epigenetic effects on asthma risk to improve our understanding of the underlying mechanisms of asthma.

The role of metabolites, nutrients, and toxins (MNTs) in sera at the end of pregnancy and of their association with offspring respiratory and allergic disorders is underexplored. Untargeted approaches detecting a variety of compounds, known and unknown, are limited. In this cohort study, we first aimed at discovering associations of MNTs in grandmaternal (F0) serum with asthma, immunoglobulin E, skin prick tests, exhaled nitric oxide, and lung function parameters in their parental (F1) offspring. Second, for replication, we tested the identified associations of MNTs with disorders in their grandchildren (F2-offspring) based on F2 cord serum. The statistical analyses were sex-stratified. Using liquid chromatography/high-resolution mass spectrometry in F0, we detected signals for 2286 negative-ion lipids, 59 positive-ion lipids, and 6331 polar MNTs. Nine MNTs (one unknown MNT) discovered in F0-F1 and replicated in F2 showed higher risks of respiratory/allergic outcomes. Twelve MNTs (four unknowns) constituted a potential protection in F1 and F2. We recognized MNTs not yet considered candidates for respiratory/allergic outcomes: a phthalate plasticizer, an antihistamine, a bile acid metabolite, tryptophan metabolites, a hemiterpenoid glycoside, triacylglycerols, hypoxanthine, and polyphenol syringic acid. The findings suggest that MNTs are aspirants for clinical trials to prevent adverse respiratory/allergic outcomes.