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      Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease.

      1 ,   2 , 3 , 4 , 1 , 5 , 6 , 1 , 7 , 7 , 8 , 8 , 1 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 1 , 29 , 30 , 30 , 31 , 32 , 31 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ,   5 , 45 , 46 , 6 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 44 , 55 , 56 , 57 , 47 , 58 , 59 , 60 , 61 , 61 , 61 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 53 , 68 , 5 , 69 , 56 , 70 , 71 , 72 , 56 , 73 , 74 , 75 , 76 , 77 , 78 , 69 , 69 , 79 , 80 , 81 , 82 , 44 , 83 ,   47 , 84 , 29 , 85 , 86 , 87 , 88 , 88 , 57 , 89 , 90 , 54 , 30 , 91 , 92 , 93 , 94 , 95 , 96 , 19 , 97 , 27 , 20 , 98 , 99 , 5 , 100 , 101
      Journal of the American College of Cardiology
      Elsevier BV
      cholesteryl ester transfer protein, expression quantitative trait loci, genetics, genome-wide association, single nucleotide polymorphism

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          Abstract

          Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits.

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          Most cited references46

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          Genetic studies of body mass index yield new insights for obesity biology.

          Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P  20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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            Discovery and Refinement of Loci Associated with Lipid Levels

            Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol are heritable, modifiable, risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,578 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5×10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian, and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipids are often associated with cardiovascular and metabolic traits including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio, and body mass index. Our results illustrate the value of genetic data from individuals of diverse ancestries and provide insights into biological mechanisms regulating blood lipids to guide future genetic, biological, and therapeutic research.
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              A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

              Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005
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                Author and article information

                Journal
                J. Am. Coll. Cardiol.
                Journal of the American College of Cardiology
                Elsevier BV
                1558-3597
                0735-1097
                Feb 21 2017
                : 69
                : 7
                Affiliations
                [1 ] Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
                [2 ] Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany; DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany; University Heart Center Luebeck, Lübeck, Germany.
                [3 ] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
                [4 ] Cardiovascular Division, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri; Department of Genetics, Washington University School of Medicine, Saint Louis, Missouri; McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, Missouri.
                [5 ] Deutsches Herzzentrum München, Technische Universität München, München, Germany; DZHK, Partner Site Munich Heart Alliance, Munich, Germany.
                [6 ] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
                [7 ] DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany; Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany.
                [8 ] Center for Population Studies, National Heart, Lung, and Blood Institute, The Framingham Heart Study, Framingham, Massachusetts.
                [9 ] Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden; Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm, Sweden.
                [10 ] Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu, Estonia; Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia; Clinical Gene Networks AB, Stockholm, Sweden.
                [11 ] Clinical Gene Networks AB, Stockholm, Sweden; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
                [12 ] Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
                [13 ] Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm, Sweden; Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu, Estonia; Clinical Gene Networks AB, Stockholm, Sweden; Department of Genetics & Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
                [14 ] Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
                [15 ] School of Public Heath, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin.
                [16 ] Fred Hutchinson Cancer Research Center, Seattle, Washington; The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York.
                [17 ] The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York.
                [18 ] Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan.
                [19 ] Université de Montréal, Faculté de médecine, Département de médecine, Montreal, Quebec, Canada; Montreal Heart Institute, Montreal, Quebec, Canada.
                [20 ] Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
                [21 ] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
                [22 ] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea.
                [23 ] The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York; The Center for Statistical Genetics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; The Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; The Zena and Michael A. Weiner Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
                [24 ] Department of Biostatistics, Academic Medical Center, Amsterdam, the Netherlands.
                [25 ] Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Hannover, Germany.
                [26 ] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
                [27 ] MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.
                [28 ] Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.
                [29 ] Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
                [30 ] Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Scotland, United Kingdom.
                [31 ] Department of Biomedical Sciences, Humanitas University, Milan, Italy; Humanitas Clinical and Research Center, Milan, Italy.
                [32 ] Niguarda Hospital, Milan, Italy.
                [33 ] Azienda Sanitaria Locale 3 San Francesco, Nuoro, Italy 3, Nuoro, Italy.
                [34 ] Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Biomedical informatics, Vanderbilt University Medical Center, Nashville, Tennessee.
                [35 ] Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
                [36 ] Klinik für Kardiologie, Pneumologie und Innere Medizin, Imland Klinik Rendsburg, Rendsburg, Germany.
                [37 ] Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
                [38 ] Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
                [39 ] McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, Missouri; Deutsches Herzzentrum München, Technische Universität München, München, Germany.
                [40 ] Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany; Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
                [41 ] HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway; St. Olav Hospital, Trondheim University Hospital, Trondheim, Norway.
                [42 ] HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway; Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway.
                [43 ] Department of Public Health and Clinical Medicine, Research Unit Skellefteå, Umeå University, Sweden.
                [44 ] Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany.
                [45 ] Research unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany.
                [46 ] DZHK, Partner Site Munich Heart Alliance, Munich, Germany; Institute Medizinische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
                [47 ] Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy.
                [48 ] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom; Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Old Road Headington, Oxford, Oxford, United Kingdom.
                [49 ] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
                [50 ] Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
                [51 ] Estonian Genome Center, University of Tartu, Tartu, Estonia; Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts; Department of Genetics, Harvard Medical School, Boston, Massachusetts; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.
                [52 ] Estonian Genome Center, University of Tartu, Tartu, Estonia.
                [53 ] Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden.
                [54 ] Estonian Genome Center, University of Tartu, Tartu, Estonia; Institute of Molecular and Cell Biology, Tartu, Estonia.
                [55 ] School of Molecular, Genetic and Population Health Sciences, University of Edinburgh, Medical School, Teviot Place, Edinburgh, Scotland, United Kingdom.
                [56 ] National Institute for Health and Welfare (THL), Helsinki, Finland.
                [57 ] Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
                [58 ] Montreal Heart Institute, Montreal, Quebec, Canada.
                [59 ] Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
                [60 ] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
                [61 ] Merck Sharp & Dohme, Rahway, New Jersey.
                [62 ] Department of Cardiology, Division Heart & Lungs, UMC Utrecht, the Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, the Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom.
                [63 ] Fred Hutchinson Cancer Research Center, Seattle, Washington.
                [64 ] Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Ohio State University, Columbus, Ohio.
                [65 ] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.
                [66 ] DZHK, Partner Site Munich Heart Alliance, Munich, Germany; Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
                [67 ] Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
                [68 ] Research unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
                [69 ] MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
                [70 ] Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom.
                [71 ] Department of Cardiology, Leiden University Medical Center, Leiden and Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.
                [72 ] Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE, Lille, France.
                [73 ] Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
                [74 ] Toulouse University School of Medicine, Toulouse, France.
                [75 ] Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Noncommunicable Diseases, Karachi, Pakistan.
                [76 ] British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
                [77 ] Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
                [78 ] Department of Epîdemiology and Public Health, University of Strasbourg, Strasbourg, France.
                [79 ] MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; National Institute of Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom.
                [80 ] MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; National Institute of Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
                [81 ] Parma University Hospital, Parma, Italy.
                [82 ] The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York.
                [83 ] Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts; Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden.
                [84 ] Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, United Kingdom.
                [85 ] Deutsches Herzzentrum München, Technische Universität München, München, Germany.
                [86 ] Institute of Epidemiology and Biobank popgen, Christian-Albrechts-University Kiel, Kiel, Germany.
                [87 ] DZHK, Partner Site Munich Heart Alliance, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany.
                [88 ] Duke Molecular Physiology Institute, Duke University, Durham, North Carolina; Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina.
                [89 ] Department of Clinical Sciences in Malmo, Lund University, Clinical Research Center, Malmo, Sweden.
                [90 ] Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmo, Malmo, Sweden.
                [91 ] DZHK, Partner Site Munich Heart Alliance, Munich, Germany; Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
                [92 ] Department of Genetics, Cardiovascular Institute and Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
                [93 ] Division of Cardiology, Department of Medicine and the Irving Institute for Clinical and Translational Research, Columbia University, New York, New York.
                [94 ] The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York; The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York.
                [95 ] Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington.
                [96 ] Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
                [97 ] NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom; Department of Health Sciences, University of Leicester, Leicester, United Kingdom.
                [98 ] Université de Montréal, Faculté de médecine, Département de médecine, Montreal, Quebec, Canada; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan.
                [99 ] Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom. Electronic address: njs@le.ac.uk.
                [100 ] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address: p.deloukas@qmul.ac.uk.
                [101 ] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts.
                Article
                S0735-1097(16)37341-7
                10.1016/j.jacc.2016.11.056
                5314135
                28209224
                096821ab-7fd5-4907-8a33-ebfd6704b342
                History

                cholesteryl ester transfer protein,expression quantitative trait loci,genetics,genome-wide association,single nucleotide polymorphism

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