Multi-omics colocalization with genome-wide association studies reveals a context-specific genetic mechanism at a childhood onset asthma risk locus
Posted on 2021-10-11 - 03:14
Abstract Background Genome-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. Methods Genome-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. Results Asthma 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. Conclusions This 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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Soliai, Marcus M.; Kato, Atsushi; Helling, Britney A.; Stanhope, Catherine T.; Norton, James E.; Naughton, Katherine A.; et al. (2021). Multi-omics colocalization with genome-wide association studies reveals a context-specific genetic mechanism at a childhood onset asthma risk locus. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.5655569.v1
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AUTHORS (20)
MS
Marcus M. Soliai
AK
Atsushi Kato
BH
Britney A. Helling
CS
Catherine T. Stanhope
JN
James E. Norton
KN
Katherine A. Naughton
AK
Aiko I. Klinger
ET
Emma E. Thompson
SC
Selene M. Clay
SK
Soyeon Kim
JC
Juan C. Celedón
JG
James E. Gern
DJ
Daniel J. Jackson
MA
Matthew C. Altman
RK
Robert C. Kern
BT
Bruce K. Tan
RS
Robert P. Schleimer
DN
Dan L. Nicolae
JP
Jayant M. Pinto
CO
Carole Ober
CATEGORIES
KEYWORDS
study provides evidencedna methylation dataepigenetic response mechanismsadult onset asthmamodulate genetic effects21 asthma locuswide association studiesused mendelian randomizationtreated upper aecsassociated gwas snpsspecific genetic mechanismspecific functional annotationschildhood onset asthmaasthma colocalized locimapped cis expressionaec molecular qtlsasthma risk variantswide geneticchildhood onsetfunctional effectsresults asthmavariants associatedtslp locusgene expressionethnic gwasepigenetic responsesepidemiological studiesspecific informationvariants discoveredtreatment conditionpromoting pathogenmediated transcriptionalincluding qtlsimmune diseasesidentified thousandshealthy participantsenvironmental factorsculture modelcomplex diseasescell typesbayesian testassess transcriptionalallergic diseaseaec qtls38 ).