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      Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease

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          Abstract

          Supplemental Digital Content is available in the text.

          Abstract

          Rationale:

          Coronary artery disease (CAD) is a complex phenotype driven by genetic and environmental factors. Ninety-seven genetic risk loci have been identified to date, but the identification of additional susceptibility loci might be important to enhance our understanding of the genetic architecture of CAD.

          Objective:

          To expand the number of genome-wide significant loci, catalog functional insights, and enhance our understanding of the genetic architecture of CAD.

          Methods and Results:

          We performed a genome-wide association study in 34 541 CAD cases and 261 984 controls of UK Biobank resource followed by replication in 88 192 cases and 162 544 controls from CARDIoGRAMplusC4D. We identified 75 loci that replicated and were genome-wide significant ( P<5×10 −8) in meta-analysis, 13 of which had not been reported previously. Next, to further identify novel loci, we identified all promising ( P<0.0001) loci in the CARDIoGRAMplusC4D data and performed reciprocal replication and meta-analyses with UK Biobank. This led to the identification of 21 additional novel loci reaching genome-wide significance ( P<5×10 −8) in meta-analysis. Finally, we performed a genome-wide meta-analysis of all available data revealing 30 additional novel loci ( P<5×10 −8) without further replication. The increase in sample size by UK Biobank raised the number of reconstituted gene sets from 4.2% to 13.9% of all gene sets to be involved in CAD. For the 64 novel loci, 155 candidate causal genes were prioritized, many without an obvious connection to CAD. Fine mapping of the 161 CAD loci generated lists of credible sets of single causal variants and genes for functional follow-up. Genetic risk variants of CAD were linked to development of atrial fibrillation, heart failure, and death.

          Conclusions:

          We identified 64 novel genetic risk loci for CAD and performed fine mapping of all 161 risk loci to obtain a credible set of causal variants. The large expansion of reconstituted gene sets argues in favor of an expanded omnigenic model view on the genetic architecture of CAD.

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          Most cited references11

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          Genomewide association analysis of coronary artery disease.

          Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P 80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease. Copyright 2007 Massachusetts Medical Society.
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            Genetics of coronary artery disease: discovery, biology and clinical translation

            The past decade has seen tremendous progress in understanding the genetic architecture of coronary artery disease (CAD). Khera and Kathiresan review research efforts that have improved our understanding of the genetic drivers of CAD, and discuss the promises and challenges of integrating genetic information into routine clinical practice.
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              Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients

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                Author and article information

                Journal
                Circ Res
                Circ. Res
                RES
                Circulation Research
                Lippincott Williams & Wilkins
                0009-7330
                1524-4571
                2 February 2018
                01 February 2018
                : 122
                : 3
                : 433-443
                Affiliations
                From the Department of Cardiology (P.v.d.H., N.V.) and Department of Genetics (P.v.d.H.), University Medical Center Groningen, University of Groningen, The Netherlands; and Durrer Center for Cardiogenetic Research, Netherlands Heart Institute, Utrecht (P.v.d.H.).
                Author notes
                Correspondence to Pim van der Harst, MD, PhD, Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands. E-mail p.van.der.harst@ 123456umcg.nl
                Article
                00012
                10.1161/CIRCRESAHA.117.312086
                5805277
                29212778
                3b56e4c5-7bab-4aed-b051-2ac56ca47002
                © 2017 The Authors.

                Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.

                History
                : 18 September 2017
                : 26 November 2017
                : 4 December 2017
                Categories
                10053
                10081
                10082
                10084
                10189
                Molecular Medicine
                Custom metadata
                TRUE

                computational biology,coronary artery disease,genetics,genome-wide association study,sample size

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