Functional noncoding SNPs in human endothelial cells fine-map vascular trait associations
Genome Res.-2022-Toropainen-40 ...
Final Published Version
AffiliationDepartment of Cellular and Molecular Medicine, University of Arizona
Genetics Interdisciplinary Graduate Program, University of Arizona
MetadataShow full item record
PublisherCold Spring Harbor Lab Press
CitationToropainen, A., Stolze, L. K., Örd, T., Whalen, M. B., Torrell, P. M., Link, V. M., Kaikkonen, M. U., & Romanoski, C. E. (2022). Functional noncoding SNPs in human endothelial cells fine-map vascular trait associations. Genome Research.
RightsCopyright © 2022 Toropainen et al. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see https://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/ 4.0/.
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AbstractFunctional consequences of genetic variation in the noncoding human genome are difficult to ascertain despite demonstrated associations to common, complex disease traits. To elucidate properties of functional noncoding SNPs with effects in human endothelial cells (ECs), we utilized our previous molecular quantitative trait locus (molQTL) analysis for transcription factor binding, chromatin accessibility, and H3K27 acetylation to nominate a set of likely functional noncoding SNPs. Together with information from genome-wide association studies (GWASs) for vascular disease traits, we tested the ability of 34,344 variants to perturb enhancer function in ECs using the highly multiplexed STARR-seq assay. Of these, 5711 variants validated, whose enriched attributes included: (1) mutations to TF binding motifs for ETS or AP-1 that are regulators of the EC state; (2) location in accessible and H3K27ac-marked EC chromatin; and (3) molQTL associations whereby alleles associate with differences in chromatin accessibility and TF binding across genetically diverse ECs. Next, using pro-inflammatory IL1B as an activator of cell state, we observed robust evidence (>50%) of context-specific SNP effects, underscoring the prevalence of noncoding gene-by-environment (GxE) effects. Lastly, using these cumulative data, we fine-mapped vascular disease loci and highlighted evidence suggesting mechanisms by which noncoding SNPs at two loci affect risk for pulse pressure/large artery stroke and abdominal aortic aneurysm through respective effects on transcriptional regulation of POU4F1 and LDAH Together, we highlight the attributes and context dependence of functional noncoding SNPs and provide new mechanisms underlying vascular disease risk. © 2022 Toropainen et al.; Published by Cold Spring Harbor Laboratory Press.
Note6 month embargo; published online: 22 February 2022
VersionFinal published version
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