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Multi-omics colocalization with genotype-wide association studies reveals a context-specific genetic mechanism at a childhood onset asthma risk locus

ABSTRACT: We generated imputed genotypes from 104 individuals from whole blood or airway epithelial cells. This data was generated in combination with genome-wide DNA methylation data (RNAseq) and genotypes from the same individuals as part of an expression and DNAm quantitatively loci study.

INSTRUMENT(S): -

ORGANISM(S): Homo Sapiens

SUBMITTER: Uchicago

PROVIDER: PRJEB47290 | EVA | 2021-09-04

REPOSITORIES: EVA

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			Action	DRS
	CRISP.imputed.genotypes.VALID.vcf.gz	Vcf
	CRISP.imputed.genotypes.VALID.vcf.gz.csi	Vcf
	CRISP.imputed.genotypes.VALID.vcf.gz.tbi	Vcf

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Project description:BackgroundGenome-wide association studies (GWASs) have identified thousands of variants associated with asthma and other complex diseases. However, the functional effects of most of these variants are unknown. Moreover, GWASs do not provide context-specific information on cell types or environmental factors that affect specific disease risks and outcomes. To address these limitations, we used an upper airway epithelial cell (AEC) culture model to assess transcriptional and epigenetic responses to rhinovirus (RV), an asthma-promoting pathogen, and provide context-specific functional annotations to variants discovered in GWASs of asthma.MethodsGenome-wide genetic, gene expression, and DNA methylation data in vehicle- and RV-treated upper AECs were collected from 104 individuals who had a diagnosis of airway disease (n=66) or were healthy participants (n=38). We mapped cis expression and methylation quantitative trait loci (cis-eQTLs and cis-meQTLs, respectively) in each treatment condition (RV and vehicle) in AECs from these individuals. A Bayesian test for colocalization between AEC molecular QTLs and adult onset asthma and childhood onset asthma GWAS SNPs, and a multi-ethnic GWAS of asthma, was used to assign the function to variants associated with asthma. We used Mendelian randomization to demonstrate DNA methylation effects on gene expression at asthma colocalized loci.ResultsAsthma and allergic disease-associated GWAS SNPs were specifically enriched among molecular QTLs in AECs, but not in GWASs from non-immune diseases, and in AEC eQTLs, but not among eQTLs from other tissues. Colocalization analyses of AEC QTLs with asthma GWAS variants revealed potential molecular mechanisms of asthma, including QTLs at the TSLP locus that were common to both the RV and vehicle treatments and to both childhood onset and adult onset asthma, as well as QTLs at the 17q12-21 asthma locus that were specific to RV exposure and childhood onset asthma, consistent with clinical and epidemiological studies of these loci.ConclusionsThis study provides evidence of functional effects for asthma risk variants in AECs and insight into RV-mediated transcriptional and epigenetic response mechanisms that modulate genetic effects in the airway and risk for asthma.

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Multi-omics colocalization with genotype-wide association studies reveals a context-specific genetic mechanism at a childhood onset asthma risk locus

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