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

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Marcus M. Soliai ◽  
Atsushi Kato ◽  
Britney A. Helling ◽  
Catherine T. Stanhope ◽  
James E. Norton ◽  
...  

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.

2019 ◽  
Author(s):  
Marcus M. Soliai ◽  
Atsushi Kato ◽  
Catherine T. Stanhope ◽  
James E. Norton ◽  
Katherine A. Naughton ◽  
...  

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.


Neurology ◽  
2010 ◽  
Vol 74 (6) ◽  
pp. 480-486 ◽  
Author(s):  
F. Zou ◽  
M. M. Carrasquillo ◽  
V. S. Pankratz ◽  
O. Belbin ◽  
K. Morgan ◽  
...  

2018 ◽  
Author(s):  
Kristin M. Mignogna ◽  
Silviu A. Bacanu ◽  
Brien P. Riley ◽  
Aaron R. Wolen ◽  
Michael F. Miles

AbstractGenome-wide association studies on alcohol dependence, by themselves, have yet to account for the estimated heritability of the disorder and provide incomplete mechanistic understanding of this complex trait. Integrating brain ethanol-responsive gene expression networks from model organisms with human genetic data on alcohol dependence could aid in identifying dependence-associated genes and functional networks in which they are involved. This study used a modification of the Edge-Weighted Dense Module Searching for genome-wide association studies (EW-dmGWAS) approach to co-analyze whole-genome gene expression data from ethanol-exposed mouse brain tissue, human protein-protein interaction databases and alcohol dependence-related genome-wide association studies. Results revealed novel ethanol-regulated and alcohol dependence-associated gene networks in prefrontal cortex, nucleus accumbens, and ventral tegmental area. Three of these networks were overrepresented with genome-wide association signals from an independent dataset. These networks were significantly overrepresented for gene ontology categories involving several mechanisms, including actin filament-based activity, transcript regulation, Wnt and Syndecan-mediated signaling, and ubiquitination. Together, these studies provide novel insight for brain mechanisms contributing to alcohol dependence.


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