title: Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci.
abstract: Coronary artery disease (CAD) is the leading cause of mortality and morbidity, driven by both genetic and environmental risk factors. Meta-analyses of genome-wide association studies have identified >150 loci associated with CAD and myocardial infarction susceptibility in humans. A majority of these variants reside in non-coding regions and are co-inherited with hundreds of candidate regulatory variants, presenting a challenge to elucidate their functions. Herein, we use integrative genomic, epigenomic and transcriptomic profiling of perturbed human coronary artery smooth muscle cells and tissues to begin to identify causal regulatory variation and mechanisms responsible for CAD associations. Using these genome-wide maps, we prioritize 64 candidate variants and perform allele-specific binding and expression analyses at seven top candidate loci: 9p21.3, SMAD3, PDGFD, IL6R, BMP1, CCDC97/TGFB1 and LMOD1. We validate our findings in expression quantitative trait loci cohorts, which together reveal new links between CAD associations and regulatory function in the appropriate disease context.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Clint L
authors.initials: CL
authors.lastname: Miller
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Milos
authors.initials: M
authors.lastname: Pjanic
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Trieu
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Ariella
authors.initials: A
authors.lastname: Cohain
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Lee
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm SE-171 77, Sweden.
authors.forename: Ljubica
authors.initials: L
authors.lastname: Perisic
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm SE-171 77, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Hedin
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Ramendra K
authors.initials: RK
authors.lastname: Kundu
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Deshna
authors.initials: D
authors.lastname: Majmudar
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Juyong B
authors.initials: JB
authors.lastname: Kim
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Wang
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala SE-751 05, Sweden.|Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm SE-171 77, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Betsholtz
authors.affiliation: Department of Cardiac Surgery, Tartu University Hospital, Tartu 50406, Estonia.|Clinical Gene Networks AB, Stockholm SE-114 44, Sweden.
authors.forename: Arno
authors.initials: A
authors.lastname: Ruusalepp
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Clinical Gene Networks AB, Stockholm SE-114 44, Sweden.
authors.forename: Oscar
authors.initials: O
authors.lastname: Franzén
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Themistocles L
authors.initials: TL
authors.lastname: Assimes
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Montgomery
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.|Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm SE-171 77, Sweden.|Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu 50406, Estonia.
authors.forename: Johan L M
authors.initials: JLM
authors.lastname: Björkegren
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
mesh_terms: D000483:Alleles; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods*; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D040641:Quantitative Trait Loci; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D018808:Transcription Factor AP-1; C491825:TCF21 protein, human