Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci

• Published in: Nature communications Vol. 7; no. 1; p. 12092
• Main Authors: Miller, Clint L., Pjanic, Milos, Wang, Ting, Nguyen, Trieu, Cohain, Ariella, Lee, Jonathan D., Perisic, Ljubica, Hedin, Ulf, Kundu, Ramendra K., Majmudar, Deshna, Kim, Juyong B., Wang, Oliver, Betsholtz, Christer, Ruusalepp, Arno, Franzén, Oscar, Assimes, Themistocles L., Montgomery, Stephen B., Schadt, Eric E., Björkegren, Johan L.M., Quertermous, Thomas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.07.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/109; 13/89; 13/95; 14; 38; 38/15; 38/22; 38/39; 38/43; 38/77; 38/90; 38/91; 42; 59; 631/208/191; 631/208/729/743; 692/499; 692/699/75/593/15; Alleles; Base Sequence; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cardiovascular disease; Chromatin - chemistry; Chromatin - metabolism; Coronary artery; Coronary artery disease; Coronary Artery Disease - genetics; Coronary Artery Disease - metabolism; Coronary Artery Disease - pathology; Coronary vessels; Coronary Vessels - metabolism; Coronary Vessels - pathology; Ecological risk assessment; Environmental risk; Gene Expression Profiling; Gene Expression Regulation; Gene mapping; Genetic analysis; Genetic Predisposition to Disease; Genome, Human; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Genomics - methods; Heart diseases; Humanities and Social Sciences; Humans; Interleukin 6; Interleukin 6 receptors; Medicin och hälsovetenskap; Morbidity; multidisciplinary; Muscles; Myocardial infarction; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Primary Cell Culture; Quantitative Trait Loci; Regulatory mechanisms (biology); Risk analysis; Risk factors; Science; Science (multidisciplinary); Smad3 protein; Smooth muscle; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - metabolism; Transforming growth factor-b1
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12092

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. Coronary heart disease is the leading cause of death worldwide with multiple environmental and genetic risk factors. Here the authors integrate genomic, epigenomic and transcriptomic mapping to elucidate causal variation and mechanisms of known genetic associations.