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dc.contributor.authorHoward, A.D.
dc.contributor.authorWang, X.
dc.contributor.authorPrasad, M.
dc.date.accessioned2019-09-13T14:49:28Z
dc.date.available2019-09-13T14:49:28Z
dc.date.issued2019
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85065337778&doi=10.1371%2fjournal.pone.0215911&partnerID=40&md5=b4c304287e9c28368dc66dc6c21398ac
dc.identifier.urihttp://hdl.handle.net/10713/10545
dc.description.abstractFor most complex traits, the majority of SNPs identified through genome-wide association studies (GWAS) reside within noncoding regions that have no known function. However, these regions are enriched for the regulatory enhancers specific to the cells relevant to the specific trait. Indeed, many of the GWAS loci that have been functionally characterized lie within enhancers that regulate expression levels of key genes. In order to identify polymorphisms with potential allele-specific regulatory effects, we developed a bioinformatics pipeline that harnesses epigenetic signatures as well as transcription factor (TF) binding motifs to identify putative enhancers containing a SNP with potential allele-specific TF binding in linkage disequilibrium (LD) with a GWAS-identified SNP. We applied the approach to GWAS findings for blood lipids, revealing 7 putative enhancers harboring associated SNPs, 3 of which lie within the introns of LCAT and ABCA1, genes that play crucial roles in cholesterol biogenesis and lipoprotein metabolism. All 3 enhancers demonstrated allele-specific in vitro regulatory activity in liver-derived cell lines. We demonstrated that these putative enhancers are in close physical proximity to the promoters of their respective genes, in situ, likely through chromatin looping. In addition, the associated alleles altered the likelihood of transcription activator STAT3 binding. Our results demonstrate that through our approach, the LD blocks that contain GWAS signals, often hundreds of kilobases in size with multiple SNPs serving as statistical proxies to the true functional site, can provide an experimentally testable hypothesis for the underlying regulatory mechanism linking genetic variants to complex traits. Copyright 2019 Howard et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.description.urihttps://doi.org/10.1371/journal.pone.0215911en_US
dc.language.isoen-USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.ispartofPLoS ONE
dc.subjectSNP
dc.subjectallele-specific enhancersen_US
dc.subject.meshPolymorphism, Single Nucleotideen_US
dc.subject.meshLipoproteins, HDLen_US
dc.titleAllele-specific enhancers mediate associations between LCAT and ABCA1 polymorphisms and HDL metabolismen_US
dc.typeArticleen_US
dc.identifier.doi10.1371/journal.pone.0215911
dc.identifier.pmid31039173


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