Rajat M Gupta1, Joseph Hadaya2, Aditi Trehan2, Seyedeh M Zekavat2, Carolina Roselli2, Derek Klarin2, Connor A Emdin2, Catharina R E Hilvering3, Valerio Bianchi3, Christian Mueller4, Amit V Khera5, Russell J H Ryan6, Jesse M Engreitz2, Robbyn Issner2, Noam Shoresh2, Charles B Epstein2, Wouter de Laat3, Jonathan D Brown7, Renate B Schnabel4, Bradley E Bernstein6, Sekar Kathiresan8. 1. Broad Institute of MIT and Harvard University, Cambridge, MA, USA; Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: rgupta@broadinstitute.org. 2. Broad Institute of MIT and Harvard University, Cambridge, MA, USA. 3. Hubrecht Institute, University Medical Center Utrecht, Utrecht, the Netherlands. 4. Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany. 5. Broad Institute of MIT and Harvard University, Cambridge, MA, USA; Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 6. Broad Institute of MIT and Harvard University, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 7. Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. 8. Broad Institute of MIT and Harvard University, Cambridge, MA, USA; Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: skathiresan1@mgh.harvard.edu.
Abstract
Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common SNP in the third intron of the PHACTR1 gene, as the putative causal variant. Epigenomic data from human tissue revealed an enhancer signature at rs9349379 exclusively in aorta, suggesting a regulatory function for this SNP in the vasculature. CRISPR-edited stem cell-derived endothelial cells demonstrate rs9349379 regulates expression of endothelin 1 (EDN1), a gene located 600 kb upstream of PHACTR1. The known physiologic effects of EDN1 on the vasculature may explain the pattern of risk for the five associated diseases. Overall, these data illustrate the integration of genetic, phenotypic, and epigenetic analysis to identify the biologic mechanism by which a common, non-coding variant can distally regulate a gene and contribute to the pathogenesis of multiple vascular diseases.
Genome-wide association studies (GWASs) implicate the an class="Gene">PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common SNP in the third intron of the PHACTR1 gene, as the putative causal variant. Epigenomic data from human tissue revealed an enhancer signature at rs9349379 exclusively in aorta, suggesting a regulatory function for this SNP in the vasculature. CRISPR-edited stem cell-derived endothelial cells demonstrate rs9349379 regulates expression of endothelin 1 (EDN1), a gene located 600 kb upstream of PHACTR1. The known physiologic effects of EDN1 on the vasculature may explain the pattern of risk for the five associated diseases. Overall, these data illustrate the integration of genetic, phenotypic, and epigenetic analysis to identify the biologic mechanism by which a common, non-coding variant can distally regulate a gene and contribute to the pathogenesis of multiple vascular diseases.
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