Dataset Information

DNA Methylation and Asthma Acquisition during Adolescence and Post-Adolescence, an Epigenome-Wide Longitudinal Study.

ABSTRACT: 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.

SUBMITTER: Rathod A

PROVIDER: S-EPMC8877984 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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DNA Methylation and Asthma Acquisition during Adolescence and Post-Adolescence, an Epigenome-Wide Longitudinal Study.

Rathod Aniruddha A Zhang Hongmei H Arshad Syed Hasan SH Ewart Susan S Relton Caroline L CL Karmaus Wilfried W Holloway John W JW

Journal of personalized medicine 20220202 2

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 t ...[more]

PMID: 35207690

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Project description:BackgroundLittle is known about the association of newborn DNA methylation (DNAm) with asthma acquisition across adolescence and early adult life.ObjectiveWe aim to identify epigenetic biomarkers in newborns for asthma acquisition during adolescence or young adulthood.MethodsThe Isle of Wight Birth Cohort (IOWBC) (n = 1456) data at ages 10, 18 and 26 years were assessed. To screen cytosine-phosphate-guanine site (CpGs) potentially associated with asthma acquisition, at the genome scale, we examined differentially methylated regions (DMR) using dmrff R package and individual CpG sites using linear regression on such associations. For CpGs that passed screening, we examined their enrichment in biological pathways using their mapping genes and tested their associations with asthma acquisitions using logistic regressions. Findings in IOWBC were tested in an independent cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.ResultsIn total, 2636 unique CpGs passed screening, based on which we identified one biological pathway linked to asthma acquisition during adolescence in females (FDR adjusted p-value = .003 in IOWBC). Via logistic regressions, for females, four CpGs were shown to be associated with asthma acquisition during adolescence, and another four CpGs with asthma acquisition in young adulthood (FDR adjusted p-value < .05 in IOWBC) and these eight CpGs were replicated in ALSPAC (all p-values < .05). DNAm at all the identified CpGs was shown to be temporally consistent, and at six of the CpGs was associated with expressions of adjacent or mapping genes in females (all p-values < .05). For males, 622 CpGs were identified in IOWBC (FDR = 0.01), but these were not tested in ALSPAC due to small sample sizes.Conclusion and clinical relevanceEight CpGs on LHX5, IL22RA2, SOX11, CBX4, ACPT, CFAP46, MUC4, and ATP1B2 genes have the potential to serve as candidate epigenetic biomarkers in newborns for asthma acquisition in females during adolescence or young adulthood.

Project description:BackgroundAsthma heritability has only been partially explained by genetic variants and is known to be sensitive to environmental factors, implicating epigenetic modifications such as DNA methylation in its pathogenesis.MethodsUsing data collected in the Avon Longitudinal Study of Parents and Children (ALSPAC), we assessed associations of asthma and wheeze with DNA methylation at 7.5 and 16.5 years, at over 450,000 CpG sites in DNA from the peripheral blood of approx. 1000 participants. We used Mendelian randomization (MR), a method of causal inference that uses genetic variants as instrumental variables, to infer the direction of association between DNA methylation and asthma.ResultsWe identified 302 CpGs associated with current asthma status (FDR-adjusted P value < 0.05) and 445 with current wheeze status at 7.5 years, with substantial overlap between the two. Genes annotated to the 302 associated CpGs were enriched for pathways related to movement of cellular/subcellular components, locomotion, interleukin-4 production and eosinophil migration. All associations attenuated when adjusted for eosinophil and neutrophil cell count estimates. At 16.5 years, two sites were associated with current asthma after adjustment for cell counts. The CpGs mapped to the AP2A2 and IL5RA genes, with a - 2.32 [95% CI - 1.47, - 3.18] and - 2.49 [95% CI - 1.56, - 3.43] difference in percentage methylation in asthma cases respectively. Two-sample bi-directional MR indicated a causal effect of asthma on DNA methylation at several CpG sites at 7.5 years. However, associations did not persist after adjustment for multiple testing. There was no evidence of a causal effect of asthma on DNA methylation at either of the two CpG sites at 16.5 years.ConclusionThe majority of observed associations are driven by higher eosinophil cell counts in asthma cases, acting as an intermediate phenotype, with important implications for future studies of DNA methylation in atopic diseases.

Project description:BackgroundDNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.MethodsWe examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.ResultsDNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10-7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10-4; adolescence Penrichment = 2.10 × 10-7).ConclusionsThere were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.

Dataset Information

DNA Methylation and Asthma Acquisition during Adolescence and Post-Adolescence, an Epigenome-Wide Longitudinal Study.

Publications

DNA Methylation and Asthma Acquisition during Adolescence and Post-Adolescence, an Epigenome-Wide Longitudinal Study.

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