PT  - JOURNAL ARTICLE
AU  - Quanyi Zhao
AU  - Michael Dacre
AU  - Trieu Nguyen
AU  - Milos Pjanic
AU  - Boxiang Liu
AU  - Dharini Iyer
AU  - Paul Cheng
AU  - Robert Wirka
AU  - Juyong Brian Kim
AU  - Hunter B Fraser
AU  - Thomas Quertermous
TI  - Quantitative trait loci mapped for TCF21 binding, chromatin accessibility and chromosomal looping in coronary artery smooth muscle cells reveal molecular mechanisms of coronary disease loci
AID  - 10.1101/2020.02.03.932368
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.02.03.932368
4099  - http://biorxiv.org/content/early/2020/02/04/2020.02.03.932368.short
4100  - http://biorxiv.org/content/early/2020/02/04/2020.02.03.932368.full
AB  - Background To investigate the epigenetic and transcriptional mechanisms of coronary artery disease (CAD) risk, as well as the functional regulation of chromatin structure and function, we have created a catalog of genetic variants associated with three stages of transcriptional cis-regulation in primary human coronary artery vascular smooth muscle cells (HCASMC).Results To this end, we have used a pooling approach with HCASMC lines to map regulatory variation that mediates binding of the CAD associated transcription factor TCF21 with ChIPseq studies (bQTLs), variation that regulates chromatin accessibility with ATACseq studies (caQTLs), and chromosomal looping with HiC methods (clQTLs). We show significant overlap of the QTLs, and their relationship to smooth muscle specific genes and the binding of smooth muscle transcription factors. Further, we use multiple analyses to show that these QTLs are highly associated with CAD GWAS loci and correlated to lead SNPs in these loci where they show allelic effects. We have verified with genome editing that identified functional variants can regulate both chromatin accessibility and chromosomal looping, providing new insights into functional mechanisms regulating chromatin state and chromosomal structure. Finally, we directly link the disease associated TGFβ1-SMAD3 pathway to the CAD associated FN1 gene through a response QTL that modulates both chromatin accessibility and chromosomal looping.Conclusions Together, these studies represent the most thorough mapping of multiple QTL types in a highly disease relevant primary cultured cell type, and provide novel insights into their functional overlap and mechanisms that underlie these genomic features and their relationship to disease risk.GWASgenome wide association studiesCADcoronary artery diseaseHCASMChuman coronary artery vascular smooth muscle cellseQTLexpression quantitative trait locusacQTLchromatin accessibility quantitative trait locusclQTLchromosomal looping quantitative trait locusLDlinkage disequilibriumAP-1activated protein 1TFtranscription factorSNPsingle nucleotide polymorphism.