Genomic profiling of human vascular cells identifies TWIST1 as a causal gene for common vascular diseases

• Published in: PLoS genetics Vol. 16; no. 1; p. e1008538
• Main Authors: Nurnberg, Sylvia T., Guerraty, Marie A., Wirka, Robert C., Rao, H. Shanker, Pjanic, Milos, Norton, Scott, Serrano, Felipe, Perisic, Ljubica, Elwyn, Susannah, Pluta, John, Zhao, Wei, Testa, Stephanie, Park, YoSon, Nguyen, Trieu, Ko, Yi-An, Wang, Ting, Hedin, Ulf, Sinha, Sanjay, Barash, Yoseph, Brown, Christopher D., Quertermous, Thomas, Rader, Daniel J.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.01.2020; Public Library of Science (PLoS)
• Subjects: Abdominal aortic aneurysm; Alleles; Aneurysm; Aorta; Aortic aneurysm; Biology and Life Sciences; Calcification; Calcification (Physiology); Cardiovascular disease; Cardiovascular diseases; Cells, Cultured; Coronary artery; Coronary heart disease; Coronary vessels; Coronary Vessels - cytology; Coronary Vessels - metabolism; Diseases; Endothelial cells; Endothelial Cells - metabolism; Endothelium; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Gene expression; Gene loci; Genes; Genetic research; Genome-wide association studies; Genomes; Genomics; Headache; Heart diseases; Humans; Immunoglobulin J Recombination Signal Sequence-Binding Protein - metabolism; Medicine; Medicine and Health Sciences; Migraine; Myocytes, Smooth Muscle - metabolism; Novels; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phenotypes; Polymorphism, Single Nucleotide; Principal components analysis; Protein Binding; Quantitative genetics; Quantitative trait loci; Smooth muscle; Software; Splicing; Stat6 protein; Supervision; Transcriptome; Twist-Related Protein 1 - genetics; Twist-Related Protein 1 - metabolism; Vascular diseases; Vascular Diseases - genetics; Yes-associated protein; Sweden; California; United Kingdom > UK; United States > US; Pennsylvania
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1008538

Genome-wide association studies have identified multiple novel genomic loci associated with vascular diseases. Many of these loci are common non-coding variants that affect the expression of disease-relevant genes within coronary vascular cells. To identify such genes on a genome-wide level, we performed deep transcriptomic analysis of genotyped primary human coronary artery smooth muscle cells (HCASMCs) and coronary endothelial cells (HCAECs) from the same subjects, including splicing Quantitative Trait Loci (sQTL), allele-specific expression (ASE), and colocalization analyses. We identified sQTLs for TARS2, YAP1, CFDP1, and STAT6 in HCASMCs and HCAECs, and 233 ASE genes, a subset of which are also GTEx eGenes in arterial tissues. Colocalization of GWAS association signals for coronary artery disease (CAD), migraine, stroke and abdominal aortic aneurysm with GTEx eGenes in aorta, coronary artery and tibial artery discovered novel candidate risk genes for these diseases. At the CAD and stroke locus tagged by rs2107595 we demonstrate colocalization with expression of the proximal gene TWIST1. We show that disrupting the rs2107595 locus alters TWIST1 expression and that the risk allele has increased binding of the NOTCH signaling protein RBPJ. Finally, we provide data that TWIST1 expression influences vascular SMC phenotypes, including proliferation and calcification, as a potential mechanism supporting a role for TWIST1 in CAD.