Abstract
Asthma 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.
Using 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 years and 16.5 years, at over 450,000 CpG sites (sites of the DNA where a cytosine can be methylated) in peripheral blood of 1000 participants. We also 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.
At 7.5 years, we identified 302 sites associated with current asthma (FDR-adjusted P-value <0.05) and 445 with current wheeze. However, all associations attenuated when adjusted for eosinophil and neutrophil cell-count estimates. Genes annotated to the 302 associated CpGs were enriched for pathways related to movement of cellular components, locomotion, IL-4 production and eosinophils. Two-sample bi-directional MR indicated a causal effect of asthma on DNA methylation at several CpG sites at 7.5 years. At 16.5 years, two sites associated with current asthma persisted after adjustment. 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] change in percentage methylation in asthma cases respectively.
The majority of 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.
- Copyright ©the authors 2017