Genetic contributions to epigenetic-defined endotypes of allergic phenotypes in children

Emma E. Thompson, Xiaoyuan Zhong, Peter Carbonetto et al. doi: https://doi.org/10.1101/2024.10.03.24314618 

Abstract

Background

Asthma is the most common chronic respiratory disease in children, but little is known about genetic contributions to its underlying endotypes. To address this gap, we studied the methylome, transcriptome, and genome from children with extensive phenotyping from birth.

Methods We performed DNA methylation (DNAm) studies using the Asthma&Allergy array and RNA-sequencing in nasal mucosal cells from 284 children (age 11 years) in the Urban Environment and Childhood Asthma (URECA) birth cohort with genotypes from whole-genome sequencing. Using empirical Bayes matrix factorization on all CpGs on the array, we derived 16 DNAm signatures and tested for associations between phenotypes and gene expression. We then replicated results in two additional cohorts and estimated the heritability of phenotype-associated signatures using single-nucleotide polymorphisms (SNPs) associated with an allergic disease, and with CpGs and genes associated with the signatures.

Overlap and number of CpGs and genes associated with DNAm signatures 5, 8, and 16.

Findings Three DNAm signatures were associated with at least one phenotype: allergic asthma, allergic rhinitis, allergic sensitization (atopy), total IgE, exhaled nitric oxide, or blood eosinophils. The genes correlated with each of the three signatures were enriched in networks reflecting inhibited immune response to microbes, impaired epithelial barrier integrity, and activated T2 immune pathways. We replicated the signature-phenotype associations in two additional birth cohorts. The estimated joint SNP heritabilities of the signatures were 0.17 (p=0.0027), 0.30 (p=9.3x10-7), and 0.16 (p=9.0x10-7), respectively.

Interpretation We identified three significantly heritable DNAm signatures defining asthma and allergy endotypes across diverse populations. Our study demonstrated that epigenetic patterning in airway mucosal cells reflects perturbations in underlying biological processes related to the development of asthma and allergic diseases in childhood.

This article is a preprint and has not been peer-reviewed. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

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