Multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci
Chani J. Hodonsky,
Adam W. Turner,
Mohammad Daud Khan,
Nelson B. Barrientos,
Ruben Methorst,
Lijiang Ma,
Nicolas G. Lopez,
Jose Verdezoto Mosquera,
Gaëlle Auguste,
Emily Farber,
Wei Feng Ma,
Doris Wong,
Suna Onengut-Gumuscu,
Maryam Kavousi,
Patricia A. Peyser,
Sander W. van der Laan,
Nicholas J. Leeper,
Jason C. Kovacic,
Johan L.M. Björkegren,
Clint L. Miller
Affiliations
Chani J. Hodonsky
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
Adam W. Turner
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
Mohammad Daud Khan
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
Nelson B. Barrientos
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA; Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
Ruben Methorst
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, the Netherlands
Lijiang Ma
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Nicolas G. Lopez
Division of Vascular Surgery, Department of Surgery, Stanford University, Stanford, CA 94305, USA
Jose Verdezoto Mosquera
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA
Gaëlle Auguste
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
Emily Farber
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
Wei Feng Ma
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA; Medical Scientist Training Program, Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA
Doris Wong
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA
Suna Onengut-Gumuscu
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
Maryam Kavousi
Department of Epidemiology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands
Patricia A. Peyser
Department of Epidemiology, University of Michigan, Ann Arbor, MI 48019, USA
Sander W. van der Laan
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, the Netherlands
Nicholas J. Leeper
Division of Vascular Surgery, Department of Surgery, Stanford University, Stanford, CA 94305, USA
Jason C. Kovacic
Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; St. Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2052, Australia
Johan L.M. Björkegren
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Huddinge, Karolinska Institutet, 141 52 Huddinge, Sweden
Clint L. Miller
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA; Division of Vascular Surgery, Department of Surgery, Stanford University, Stanford, CA 94305, USA; Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA; Corresponding author
Summary: Genome-wide association studies (GWASs) have identified hundreds of risk loci for coronary artery disease (CAD). However, non-European populations are underrepresented in GWASs, and the causal gene-regulatory mechanisms of these risk loci during atherosclerosis remain unclear. We incorporated local ancestry and haplotypes to identify quantitative trait loci for expression (eQTLs) and splicing (sQTLs) in coronary arteries from 138 ancestrally diverse Americans. Of 2,132 eQTL-associated genes (eGenes), 47% were previously unreported in coronary artery; 19% exhibited cell-type-specific expression. Colocalization revealed subgroups of eGenes unique to CAD and blood pressure GWAS. Fine-mapping highlighted additional eGenes, including TBX20 and IL5. We also identified sQTLs for 1,690 genes, among which TOR1AIP1 and ULK3 sQTLs demonstrated the importance of evaluating splicing to accurately identify disease-relevant isoform expression. Our work provides a patient-derived coronary artery eQTL resource and exemplifies the need for diverse study populations and multifaceted approaches to characterize gene regulation in disease processes.
