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Interweaving Between Genetic and Epigenetic Studies on Childhood Asthma.

ABSTRACT: 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 (r 2?

SUBMITTER: Rathod A

PROVIDER: S-EPMC7378715 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Interweaving Between Genetic and Epigenetic Studies on Childhood Asthma.

Rathod Aniruddha A Duan Jiasong J Zhang Hongmei H Holloway John W JW Ewart Susan S Arshad S Hasan SH Karmaus Wilfried W

Epigenetics insights 20200722

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 methylatio ...[more]

PMID: 32754683

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Project description:BackgroundGenome-wide association studies of asthma have revealed robust associations with variation across the human leukocyte antigen (HLA) complex with independent associations in the HLA class I and class II regions for both childhood-onset asthma (COA) and adult-onset asthma (AOA). However, the specific variants and genes contributing to risk are unknown.MethodsWe used Bayesian approaches to perform genetic fine-mapping for COA and AOA (n=9432 and 21,556, respectively; n=318,167 shared controls) in White British individuals from the UK Biobank and to perform expression quantitative trait locus (eQTL) fine-mapping in immune (lymphoblastoid cell lines, n=398; peripheral blood mononuclear cells, n=132) and airway (nasal epithelial cells, n=188) cells from ethnically diverse individuals. We also examined putatively causal protein coding variation from protein crystal structures and conducted replication studies in independent multi-ethnic cohorts from the UK Biobank (COA n=1686; AOA n=3666; controls n=56,063).ResultsGenetic fine-mapping revealed both shared and distinct causal variation between COA and AOA in the class I region but only distinct causal variation in the class II region. Both gene expression levels and amino acid variation contributed to risk. Our results from eQTL fine-mapping and amino acid visualization suggested that the HLA-DQA1*03:01 allele and variation associated with expression of the nonclassical HLA-DQA2 and HLA-DQB2 genes accounted entirely for the most significant association with AOA in GWAS. Our studies also suggested a potentially prominent role for HLA-C protein coding variation in the class I region in COA. We replicated putatively causal variant associations in a multi-ethnic cohort.ConclusionsWe highlight roles for both gene expression and protein coding variation in asthma risk and identified putatively causal variation and genes in the HLA region. A convergence of genomic, transcriptional, and protein coding evidence implicates the HLA-DQA2 and HLA-DQB2 genes and HLA-DQA1*03:01 allele in AOA.

Dataset Information

Interweaving Between Genetic and Epigenetic Studies on Childhood Asthma.

Publications

Interweaving Between Genetic and Epigenetic Studies on Childhood Asthma.

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