Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci

Clint L. Miller (), Milos Pjanic, Ting Wang, Trieu Nguyen, Ariella Cohain, Jonathan D. Lee, Ljubica Perisic, Ulf Hedin, Ramendra K. Kundu, Deshna Majmudar, Juyong B. Kim, Oliver Wang, Christer Betsholtz, Arno Ruusalepp, Oscar Franzén, Themistocles L. Assimes, Stephen B. Montgomery, Eric E. Schadt, Johan L.M. Björkegren and Thomas Quertermous ()
Additional contact information
Clint L. Miller: Stanford University School of Medicine
Milos Pjanic: Stanford University School of Medicine
Ting Wang: Stanford University School of Medicine
Trieu Nguyen: Stanford University School of Medicine
Ariella Cohain: Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
Jonathan D. Lee: Stanford University School of Medicine
Ljubica Perisic: Karolinska Institutet
Ulf Hedin: Karolinska Institutet
Ramendra K. Kundu: Stanford University School of Medicine
Deshna Majmudar: Stanford University School of Medicine
Juyong B. Kim: Stanford University School of Medicine
Oliver Wang: Stanford University School of Medicine
Christer Betsholtz: Genetics and Pathology, Rudbeck Laboratory, Uppsala University
Arno Ruusalepp: Tartu University Hospital
Oscar Franzén: Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
Themistocles L. Assimes: Stanford University School of Medicine
Stephen B. Montgomery: Stanford University School of Medicine
Eric E. Schadt: Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
Johan L.M. Björkegren: Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
Thomas Quertermous: Stanford University School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12092

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