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[Preprint]. 2024 Oct 4:2024.10.03.24314618.
doi: 10.1101/2024.10.03.24314618.

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

Emma E Thompson  1 , Xiaoyuan Zhong  1 , Peter Carbonetto  1 , Andréanne Morin  1 , Jason Willwerscheid  2 , Cynthia M Visness  3 , Leonard B Bacharier  4 , Meyer Kattan  5 , George T O'Connor  6 , Katherine Rivera-Spoljaric  7 , Robert A Wood  8 , Diane R Gold  9 , Gurjit K Khurana Hershey  10 , Christine C Johnson  11 , Rachel L Miller  12 , Christine M Seroogy  13 , Edward M Zoratti  14 , Peter J Gergen  15 , Albert M Levin  11   16 , Matthew C Altman  17 , Tina Hartert  18 , Matthew Stephens  1 , Daniel J Jackson  13 , James E Gern  13 , Christopher G McKennan  19 , Carole Ober  1
Affiliations

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

Emma E Thompson et al. medRxiv. .

Update in

  • Genetic contributions to epigenetic-defined endotypes of allergic phenotypes in children.
    Thompson EE, Zhong X, Carbonetto P, Morin A, Willwerscheid J, Visness CM, Bacharier LB, Kattan M, O'Connor GT, Rivera-Spoljaric K, Wood RA, Gold DR, Khurana Hershey GK, Johnson CC, Miller RL, Seroogy CM, Zoratti EM, Gergen PJ, Levin AM, Altman MC, Hartert T, Stephens M, Jackson DJ, Gern JE, McKennan CG, Ober C. Thompson EE, et al. Am J Hum Genet. 2025 Jul 3;112(7):1610-1624. doi: 10.1016/j.ajhg.2025.05.006. Am J Hum Genet. 2025. PMID: 40614707 Free PMC article.

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.

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=9.3×10-7), and 0.16 (p=9.0×10-7), 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.

Funding: National Institute of Allergy and Infectious Diseases and the National Institutes of Health, Office of the Director.

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Conflict of interest statement

Declaration of interests Dr. Bacharier is a member of the GINA Science Committee; reports grants from NIH/NIAID/NHLBI, personal fees from GlaxoSmithKline, Genentech/Novartis, Merck, Teva, Boehringer Ingelheim, AstraZeneca, Avillion, WebMD/Medscape, Sanofi/Regeneron, Vectura, Circassia, OM Pharma and Kinaset, for DSMB from AstraZeneca, DBV Technologies, and Vertex; and royalties from Elesvier outside the submitted work. Dr. Wood receives research support from the NIH, Aimmune, ALK, DBV, Genentech, Novartis, Siolta, and FARE, and consulting fees from Genentech. Dr. Zoratti reported grants from NIH during the conduct of the study. Dr. Hartert reported grants from NIH and the World Health Organization during the conduct of the study and personal fees from the American Thoracic Society, Parker B. Francis Council of Scientific Advisors, Pfizer and Sanofi-Pasteur outside the submitted work. Dr. Stephens reported grants from the NIH during the conduct of the study Dr. Jackson has received funding from GlaxoSmithKline and Regeneron; personal fees for Data and Safety Monitoring Board from Pfizer and AstraZeneca; and personal fees for consulting from AstraZeneca, Avillion, GlaxoSmithKline, Sanofi, and Regeneron. Dr. Gern reported grants from NIH during the conduct of the study, personal fees from Arrowhead Pharmaceuticals, AstraZeneca, and Meissa Vaccines Inc., and stock options for Meissa Vaccines Inc. outside the submitted work. Dr. McKennan reported grants from the NIH during the conduct of the study and personal fees from SignatureDx outside the submitted work. Dr. Ober reported grants from the NIH during the conduct of the study. All other authors report no conflicts of interest.

Figures

Figure 1.
Figure 1.. Overlap and number of CpGs and genes associated with DNAm signatures 5, 8, and 16.
A) 7,761 out of 10,813 (71.8%) CpGs assigned to a signature (lfsr<0.05) are unique to only one signature; 4.2% are shared by all three. B) 4,852 out of 8,543 (56.8%) genes correlated (FDR<0.05) with at least one of the signatures are unique to only one signature; 8.7% are shared by all three.
Figure 2.
Figure 2.. Significant upstream regulators of genes correlated with DNAm signatures 5, 8, and 16 (FDR<0.05).
A) Interferon gamma (IFNG) is an upstream regulator of genes correlated with DNAm signature 5 (mean log2FC=−1.76; p=1.46 × 10−4). GATA binding protein 2 (GATA2) is downstream of IFNG and significantly activated in children with atopy. B) Septin-2 (SEPTIN2) is an upstream regulator of genes correlated with DNAm signature 8 (mean log2FC=−2.58; p=6.67 × 10−16). Tectonic family member 2 (TCTN2) is downstream of SEPTIN2 and significantly inhibited in children with atopy. C) Interleukin 13 (IL-13) is an upstream regulator of gene correlated with DNAm signature 16 (mean log2FC=5.46; p=0.002). Periostin (POSTN) is downstream of IL13 and significantly activated in children with atopy. Scatterplots show the correlation between expression of representative genes from each network (y-axis) and the individual scores for each DNAm signature (x-axis). The red arrow denotes the direction of the correlation with atopy in URECA subjects. The residuals shown in the scatterplots (y-axes) are after regressing out site, sequencing batch, ancestry PCs 1–3, and percent squamous and percent ciliated epithelial cells as covariates (Supplementary Methods). FDR-adjusted P-values are shown. Red symbols = activated genes; blue symbols = inhibited genes; gray symbols = not differentially expressed.
Figure 3.
Figure 3.. Heritability of the DNAm signatures.
A) QQ plots of GWAS p-values (upper panel) and enrichment p-values (lower panel) for each signature. Genomic inflation factors, or lambdas (λ), were calculated based on all SNPs (black points). B) The contribution of each set of SNPs to the heritability of each signature. The total heritability of each signature was 0.17 (p=0.0026) for Signature 5, 0.30 (p=9.3×10−7) for Signature 8, and 0.16 (p=9.0×10−7) for Signature 16. C) The per-SNP contribution to the heritability of each signature.
See this image and copyright information in PMC

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