Biology subjects

Findley, A. S.

Publications and source records attributed to Findley, A. S..

3 recordsLinked to original sources

bioRxiv2022

Characterization of caffeine response regulatory variants in vascular endothelial cells

Genetic variants in gene regulatory sequences can modify gene expression and mediate the molecular response to environmental stimuli. In addition, genotype-environment interactions (GxE) contribute to complex traits such as cardiovascular disease. Caffeine is the most widely consumed stimulant and is known to produce a vascular response. To investigate GxE for caffeine, we treated vascular endothelial cells with caffeine and used a massively parallel reporter assay to measure allelic effects on gene regulation for over 43,000 genetic variants. We identified 665 variants with allelic effects on gene regulation and 29 variants that regulate the gene expression response to caffeine (GxE, FDR<10%). When overlapping our GxE results with eQTLs colocalized with CAD and hypertension, we dissected their regulatory mechanisms and showed a modulatory role for caffeine. Our results demonstrate that massively parallel reporter assay is a powerful approach to identify and molecularly characterize GxE in the specific context of caffeine consumption.

genomics↗

bioRxiv2021

Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions

Genetic effects on gene expression and splicing can be modulated by cellular and environmental factors; yet interactions between genotypes, cell type and treatment have not been comprehensively studied together. We used an induced pluripotent stem cell system to study multiple cell types derived from the same individuals and exposed them to a large panel of treatments. Cellular responses involved different genes and pathways for gene expression and splicing processes, and were also highly variable across cell types and treatments. For thousands of genes, we identified variable allelic expression across contexts, and characterized different types of gene-environment interactions. Many of these GxE genes are associated with complex traits. We characterized promoter functional and evolutionary features that distinguish genes with elevated allelic imbalance mean and variance. More than 47% of the genes with dynamic regulatory interactions were missed by GTEx, but we identified them using a suitable allelic imbalance study design. This indicates the importance of exploring multiple treatments to reveal previously unrecognized regulatory loci that may be important for disease.

genomics↗

bioRxiv2018

Interpreting coronary artery disease risk through gene-environment interactions in gene regulation

GWAS and eQTL studies identified thousands of genetic variants associated with complex traits and gene expression. Despite the important role of environmental exposures in complex traits, only a limited number of environmental factors are measured in these studies. Measuring molecular phenotypes in tightly controlled cellular environments provides a more tractable setting to study gene-environment interactions in the absence of other confounding variables.\n\nWe performed RNA-seq and ATAC-seq in endothelial cells exposed to retinoic acid, dexamethasone, caffeine, and selenium to model genetic and environmental effects on gene regulation in the vascular endothelium, a common site of pathology in cardiovascular disease. We found that genes near regions of differentially accessible chromatin were more likely to be differentially expressed (OR = [3.41, 6.52], p < 10-16). Furthermore, we confirmed that environment-specific changes in transcription factor binding are a key mechanism for cellular response to environmental stimuli. SNPs in these transcription response factor footprints for dexamethasone, caffeine, and retinoic acid were enriched in GTEx eQTLs from artery tissues indicating that these environmental conditions are latently present in GTEx samples. Additionally, SNPs in footprints for response factors in caffeine are enriched in colocalized eQTLs for coronary artery disease (CAD), suggesting a role for caffeine in CAD risk. Interestingly, each treatment may amplify or buffer genetic risk for CAD, depending on the particular SNP considered.

genomics↗