Multi-omics co-localization with genome-wide association studies reveals a context-specific genetic mechanism at a childhood onset asthma risk locus

AbstractBackgroundGenome-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 (sinonasal) epithelial cell culture model to assess transcriptional and epigenetic responses to an asthma-promoting pathogen, rhinovirus (RV), and provide context-specific functional annotations to variants discovered in GWASs of asthma.MethodsUsing genome-wide genetic, gene expression and DNA methylation data in vehicle- and RV-treated airway epithelial cells (AECs) from 104 individuals, we mapped cis expression and methylation quantitative trait loci (cis-eQTLs and cis-meQTLs, respectively) in each condition. A Bayesian test for co-localization between AEC molecular QTLs and adult onset and childhood onset GWAS variants was used to assign function to variants associated with asthma. Mendelian randomization was applied to demonstrate DNA methylation effects on gene expression at asthma colocalized loci.ResultsCo-localization analyses of airway epithelial cell molecular QTLs with asthma GWAS variants revealed potential molecular disease mechanisms of asthma, including QTLs at the TSLP locus that were common to both exposure conditions and to both childhood 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.ConclusionThis study provides information on functional effects of asthma risk variants in airway epithelial cells and insight into a disease-relevant viral exposure that modulates genetic effects on transcriptional and epigenetic responses in cells and on risk for asthma in GWASs.

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

Genome Medicine ◽

10.1186/s13073-021-00967-y ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Marcus M. Soliai ◽

Atsushi Kato ◽

Britney A. Helling ◽

Catherine T. Stanhope ◽

James E. Norton ◽

...

Keyword(s):

Gene Expression ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Adult Onset ◽

Childhood Onset ◽

Gwas Snps ◽

Asthma Risk ◽

Genome Wide ◽

Context Specific

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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Shared and Distinct Genetic Risk Factors for Childhood Onset and Adult Onset Asthma: Genome- and Transcriptome-wide Studies

10.1101/427427 ◽

2018 ◽

Cited By ~ 1

Author(s):

Milton Pividori ◽

Nathan Schoettler ◽

Dan L. Nicolae ◽

Carole Ober ◽

Hae Kyung Im

Keyword(s):

Risk Factors ◽

Genetic Risk ◽

Age Of Onset ◽

Association Studies ◽

Genetic Risk Factors ◽

Genome Wide Association Studies ◽

Adult Onset ◽

Childhood Onset ◽

Large Samples ◽

Genome Wide

BackgroundChildhood and adult onset asthma differ with respect to severity and co-morbidities. Whether they also differ with respect to genetic risk factors has not been previously investigated in large samples. The goals of this study were to identify shared and distinct genetic risk loci for childhood and adult onset asthma, and the genes that may mediate the effects of associated variation.MethodsWe used data from UK Biobank to conduct genome-wide association studies (GWASs) in 37,846 subjects with asthma, including 9,433 childhood onset cases (onset before age 12) and 21,564 adult onset cases (onset between ages 26 and 65), and 318,237 subjects without asthma (controls; older than age 38). We conducted GWASs for childhood onset asthma and adult onset asthma each compared to shared controls, and for age of asthma onset in all 37,846 asthma cases. Enrichment studies determined the tissues in which genes at GWAS loci were most highly expressed, and PrediXcan, a transcriptome-wide gene-based test, was used to identify candidate risk genes.FindingsWe detected 61 independent asthma loci: 23 were childhood onset specific, one was adult onset specific, and 37 were shared. Nineteen loci were associated with age of asthma onset. Genes at the childhood onset loci were most highly expressed in skin, blood and small intestine; genes at the adult onset loci were most highly expressed in lung, blood, small intestine and spleen. PrediXcan identified 113 unique candidate genes at 22 of the 61 GWAS loci.InterpretationGenetic risk factors for adult onset asthma are largely a subset of the genetic risk for childhood onset asthma but with overall smaller effects, suggesting a greater role for non-genetic risk factors in adult onset asthma. In contrast, the onset of disease in childhood is associated with additional genes with relatively large effect sizes, and SNP-based heritability estimates that are over 3-times larger than for adult onset disease. Combined with gene expression and tissue enrichment patterns, we suggest that the establishment of disease in children is driven more by dysregulated allergy and epithelial barrier function genes whereas the etiology of adult onset asthma is more lung-centered and environmentally determined, but with immune mediated mechanisms driving disease progression in both children and adults.FundingThis work was supported by the National Institutes of Health grants R01 MH107666 and P30 DK20595 to HKI, R01 HL129735, R01 HL122712, P01 HL070831, and UG3 OD023282 to CO; NS was supported by T32 HL007605.Research in ContextEvidence before this studyGenome-wide association studies in large samples that include both childhood onset and adult onset asthma have identified many loci associated with asthma risk. However, little was known about the shared or distinct effects of those or other loci on age of asthma onset, or about the genes that may mediate the effects of loci associated with childhoon and/or adult onset asthma.Added value of this studyLeveraging the resources of UK Biobank, we identified loci with both age of onset specific effects and shared effects. We further showed a significantly greater contribution of genetic variation to childhood onset asthma, implying a greater role for environmental risk factors in adult onset asthma, and different biological pathways and tissue enrichments for genes at loci associated with childhood vs adult onset asthma.Implications of all the available evidenceOur results suggest that childhood onset specific loci and those associated with age of onset play a role in disease initiation, whereas the other associated loci reflect shared mechanisms of disease progression. The childhood onset specific loci highlight skin as a primiary target tissue for early onset disease and support the idea that asthma in childhood is due to impaired barrier function in the skin and other epithelial surfaces.

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