Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci

Vinicius Tragante¹, Michael R Barnes², Santhi K Ganesh³, Matthew B Lanktree⁴, Wei Guo⁵, Nora Franceschini⁶, Erin N Smith⁷, Toby Johnson⁸, Michael V Holmes⁹, Sandosh Padmanabhan¹⁰, Konrad J Karczewski¹¹, Berta Almoguera¹², John Barnard¹³, Jens Baumert¹⁴, Yen-Pei Christy Chang¹⁵, Clara C Elbers¹⁶, Martin Farrall¹⁷, Mary E Fischer¹⁸, Tom R Gaunt¹⁹, Johannes M I H Gho²⁰, Christian Gieger²¹, Anuj Goel¹⁷, Yan Gong²², Aaron Isaacs²³, Marcus E Kleber²⁴, Irene Mateo Leach²⁵, Caitrin W McDonough²², Matthijs F L Meijs²⁰, Olle Melander²⁶, Christopher P Nelson²⁷, Ilja M Nolte²⁸, Nathan Pankratz²⁹, Tom S Price³⁰, Jonathan Shaffer³¹, Sonia Shah³², Maciej Tomaszewski³³, Peter J van der Most²⁸, Erik P A Van Iperen³⁴, Judith M Vonk²⁸, Kate Witkowska⁸, Caroline O L Wong⁸, Li Zhang¹³, Amber L Beitelshees³⁵, Gerald S Berenson³⁶, Deepak L Bhatt³⁷, Morris Brown³⁸, Amber Burt³⁹, Rhonda M Cooper-DeHoff²², John M Connell⁴⁰, Karen J Cruickshanks⁴¹, Sean P Curtis⁴², George Davey-Smith¹⁹, Christian Delles⁴³, Ron T Gansevoort⁴⁴, Xiuqing Guo⁴⁵, Shen Haiqing³⁵, Claire E Hastie⁴³, Marten H Hofker⁴⁶, G Kees Hovingh⁴⁷, Daniel S Kim⁴⁸, Susan A Kirkland⁴⁹, Barbara E Klein¹⁸, Ronald Klein¹⁸, Yun R Li¹², Steffi Maiwald⁴⁷, Christopher Newton-Cheh⁵⁰, Eoin T O'Brien⁵¹, N Charlotte Onland-Moret¹⁶, Walter Palmas³¹, Afshin Parsa³⁵, Brenda W Penninx⁵², Mary Pettinger⁵³, Ramachandran S Vasan⁵⁴, Jane E Ranchalis³⁹, Paul M Ridker⁵⁵, Lynda M Rose⁵⁶, Peter Sever⁵⁷, Daichi Shimbo³¹, Laura Steele⁹, Ronald P Stolk²⁸, Barbara Thorand¹⁴, Mieke D Trip⁵⁸, Cornelia M van Duijn²³, W Monique Verschuren⁵⁹, Cisca Wijmenga⁶⁰, Sharon Wyatt⁶¹, J Hunter Young⁶², Aeilko H Zwinderman⁶³, Connie R Bezzina⁶⁴, Eric Boerwinkle⁶⁵, Juan P Casas⁶⁶, Mark J Caulfield⁸, Aravinda Chakravarti⁶⁷, Daniel I Chasman⁵⁵, Karina W Davidson⁶⁸, Pieter A Doevendans²⁰, Anna F Dominiczak¹⁰, Garret A FitzGerald⁶⁹, John G Gums⁷⁰, Myriam Fornage⁷¹, Hakon Hakonarson⁷², Indrani Halder⁷³, Hans L Hillege²⁵, Thomas Illig⁷⁴, Gail P Jarvik⁵⁷, Julie A Johnson²², John J P Kastelein⁴⁷, Wolfgang Koenig⁷⁵, Meena Kumari⁷⁶, Winfried März⁷⁷, Sarah S Murray⁷⁸, Jeffery R O'Connell³⁵, Albertine J Oldehinkel⁷⁹, James S Pankow⁸⁰, Daniel J Rader⁸¹, Susan Redline⁸², Muredach P Reilly⁸¹, Eric E Schadt⁸³, Kandice Kottke-Marchant⁸⁴, Harold Snieder²⁸, Michael Snyder¹¹, Alice V Stanton⁸⁵, Martin D Tobin⁸⁶, André G Uitterlinden⁸⁷, Pim van der Harst⁸⁸, Yvonne T van der Schouw⁸⁹, Nilesh J Samani²⁷, Hugh Watkins¹⁷, Andrew D Johnson⁹⁰, Alex P Reiner⁵³, Xiaofeng Zhu⁵, Paul I W de Bakker⁹¹, Daniel Levy⁹², Folkert W Asselbergs⁹³, Patricia B Munroe⁹⁴, Brendan J Keating⁹⁵

Affiliations

¹ Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; Department of Medical Genetics, Biomedical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
² William Harvey Research Institute National Institute for Health Biomedical Research Unit, Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK.
³ Division of Cardiovascular Medicine, Departments of Internal Medicine and Human Genetics, University of Michigan Health System, Ann Arbor, MI 48109, USA.
⁴ Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁵ Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
⁶ Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁷ Department of Pediatrics and Rady's Children's Hospital, University of California at San Diego, School of Medicine, La Jolla, CA 92093, USA.
⁸ Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
⁹ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁰ BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, UK.
¹¹ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹² Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
¹³ Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
¹⁴ Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany.
¹⁵ Departments of Medicine and Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
¹⁶ Department of Medical Genetics, Biomedical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
¹⁷ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
¹⁸ Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI 53726, USA.
¹⁹ MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
²⁰ Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
²¹ Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany.
²² Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida, Gainesville, FL 32610, USA.
²³ Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
²⁴ Medical Clinic V, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany.
²⁵ Department of Cardiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
²⁶ Hypertension and Cardiovascular Disease, Department of Clinical Sciences, Lund University, Malmö 20502, Sweden; Centre of Emergency Medicine, Skåne University Hospital, Malmö 20502, Sweden.
²⁷ Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.
²⁸ Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
²⁹ Institute of Human Genetics, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
³⁰ MRC SGDP Centre, Institute of Psychiatry, London SE5 8AF, UK.
³¹ Department of Medicine, Columbia University, New York, NY 10032, USA.
³² UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, Kathleen Lonsdale Building, Gower Place, London WC1E 6BT, UK.
³³ Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK.
³⁴ Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, 3511 GC Utrecht, the Netherlands; Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
³⁵ Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
³⁶ Department of Epidemiology, Tulane University, New Orleans, LA 70118, USA.
³⁷ Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
³⁸ Clinical Pharmacology Unit, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QQ, UK.
³⁹ Department of Medicine (Medical Genetics), University of Washington, Seattle, WA 98195, USA.
⁴⁰ University of Dundee, Ninewells Hospital &Medical School, Dundee DD1 9SY, UK.
⁴¹ Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI 53726, USA; Department of Population Health Sciences, University of Wisconsin, Madison, WI 53726, USA.
⁴² Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA.
⁴³ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK.
⁴⁴ Division of Nephrology, Department of Medicine, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
⁴⁵ Cedars-Sinai Med Ctr-PEDS, Los Angeles, CA 90048, USA.
⁴⁶ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; Department Pathology and Medical Biology, Medical Biology Division, Molecular Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
⁴⁷ Department of Vascular Medicine, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
⁴⁸ Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, WA 98195, USA.
⁴⁹ Department of Community Health and Epidemiology, Dalhousie University, Halifax, NS B3H 1V7, Canada.
⁵⁰ Broad Institute of Harvard and MIT, Massachusetts General Hospital, Boston, MA 02142, USA.
⁵¹ Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
⁵² Department of Psychiatry/EMGO Institute, VU University Medical Centre, 1081 BT Amsterdam, the Netherlands.
⁵³ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁵⁴ Department of Medicine, Boston University School of Medicine, Framingham, MA 02118, USA.
⁵⁵ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
⁵⁶ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁵⁷ International Centre for Circulatory Health, Imperial College London, W2 1LA UK.
⁵⁸ Department of Cardiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
⁵⁹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, the Netherlands.
⁶⁰ Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
⁶¹ Schools of Nursing and Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁶² Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶³ Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
⁶⁴ Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands; Molecular and Experimental Cardiology Group, Academic Medical Centre, 1105 AZ Amsterdam, the Netherlands.
⁶⁵ Human Genetics Center and Institute of Molecular Medicine and Division of Epidemiology, University of Texas Health Science Center, Houston, TX 77030, USA.
⁶⁶ Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK; Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK.
⁶⁷ Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶⁸ Departments of Medicine & Psychiatry, Columbia University, New York, NY 10032, USA.
⁶⁹ The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷⁰ Departments of Pharmacotherapy and Translational Research and Community Health and Family Medicine, University of Florida, Gainesville, FL 32610, USA.
⁷¹ Institute of Molecular Medicine and School of Public Health Division of Epidemiology Human Genetics and Environmental Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁷² Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷³ School of Medicine, University of Pittsburgh, PA 15261, USA.
⁷⁴ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; Hannover Unified Biobank, Hannover Medical School, Hannover 30625, Germany.
⁷⁵ Department of Internal Medicine II - Cardiology, University of Ulm Medical Centre, Ulm 89081, Germany.
⁷⁶ Department of Epidemiology and Public Health, Division of Population Health, University College London, Torrington Place, London WC1E 7HB, UK.
⁷⁷ Medical Clinic V, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany; Synlab Academy, Synlab Services GmbH, Mannheim 69214, Germany; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8036, Austria.
⁷⁸ Department of Pathology, University of California San Diego, La Jolla, CA 92037, USA.
⁷⁹ Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
⁸⁰ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55454, USA.
⁸¹ Cardiovascular Institute, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸² Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
⁸³ Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
⁸⁴ Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
⁸⁵ Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland.
⁸⁶ Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK.
⁸⁷ Departments of Epidemiology and Internal Medicine, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
⁸⁸ Department of Cardiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, 3511 GC Utrecht, the Netherlands; Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
⁸⁹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
⁹⁰ National Heart, Lung and Blood Institute Framingham Heart Study, Framingham, MA 01702, USA.
⁹¹ Department of Medical Genetics, Biomedical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA and Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁹² Center for Population Studies, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA.
⁹³ Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, 3511 GC Utrecht, the Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London WC1E 6BT, UK.
⁹⁴ Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK. Electronic address: p.b.munroe@qmul.ac.uk.
⁹⁵ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: bkeating@mail.med.upenn.edu.

PMID: 24560520
PMCID: PMC3951943
DOI: 10.1016/j.ajhg.2013.12.016

Meta-Analysis

Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci

Vinicius Tragante et al. Am J Hum Genet. 2014.

. 2014 Mar 6;94(3):349-60.

doi: 10.1016/j.ajhg.2013.12.016. Epub 2014 Feb 20.

Authors

Affiliations

¹ Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; Department of Medical Genetics, Biomedical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
² William Harvey Research Institute National Institute for Health Biomedical Research Unit, Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK.
³ Division of Cardiovascular Medicine, Departments of Internal Medicine and Human Genetics, University of Michigan Health System, Ann Arbor, MI 48109, USA.
⁴ Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁵ Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
⁶ Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁷ Department of Pediatrics and Rady's Children's Hospital, University of California at San Diego, School of Medicine, La Jolla, CA 92093, USA.
⁸ Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
⁹ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁰ BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, UK.
¹¹ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹² Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
¹³ Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
¹⁴ Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany.
¹⁵ Departments of Medicine and Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
¹⁶ Department of Medical Genetics, Biomedical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
¹⁷ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
¹⁸ Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI 53726, USA.
¹⁹ MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
²⁰ Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
²¹ Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany.
²² Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida, Gainesville, FL 32610, USA.
²³ Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
²⁴ Medical Clinic V, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany.
²⁵ Department of Cardiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
²⁶ Hypertension and Cardiovascular Disease, Department of Clinical Sciences, Lund University, Malmö 20502, Sweden; Centre of Emergency Medicine, Skåne University Hospital, Malmö 20502, Sweden.
²⁷ Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.
²⁸ Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
²⁹ Institute of Human Genetics, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
³⁰ MRC SGDP Centre, Institute of Psychiatry, London SE5 8AF, UK.
³¹ Department of Medicine, Columbia University, New York, NY 10032, USA.
³² UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, Kathleen Lonsdale Building, Gower Place, London WC1E 6BT, UK.
³³ Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK.
³⁴ Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, 3511 GC Utrecht, the Netherlands; Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
³⁵ Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
³⁶ Department of Epidemiology, Tulane University, New Orleans, LA 70118, USA.
³⁷ Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
³⁸ Clinical Pharmacology Unit, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QQ, UK.
³⁹ Department of Medicine (Medical Genetics), University of Washington, Seattle, WA 98195, USA.
⁴⁰ University of Dundee, Ninewells Hospital &Medical School, Dundee DD1 9SY, UK.
⁴¹ Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI 53726, USA; Department of Population Health Sciences, University of Wisconsin, Madison, WI 53726, USA.
⁴² Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA.
⁴³ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK.
⁴⁴ Division of Nephrology, Department of Medicine, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
⁴⁵ Cedars-Sinai Med Ctr-PEDS, Los Angeles, CA 90048, USA.
⁴⁶ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; Department Pathology and Medical Biology, Medical Biology Division, Molecular Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
⁴⁷ Department of Vascular Medicine, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
⁴⁸ Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, WA 98195, USA.
⁴⁹ Department of Community Health and Epidemiology, Dalhousie University, Halifax, NS B3H 1V7, Canada.
⁵⁰ Broad Institute of Harvard and MIT, Massachusetts General Hospital, Boston, MA 02142, USA.
⁵¹ Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
⁵² Department of Psychiatry/EMGO Institute, VU University Medical Centre, 1081 BT Amsterdam, the Netherlands.
⁵³ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁵⁴ Department of Medicine, Boston University School of Medicine, Framingham, MA 02118, USA.
⁵⁵ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
⁵⁶ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁵⁷ International Centre for Circulatory Health, Imperial College London, W2 1LA UK.
⁵⁸ Department of Cardiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
⁵⁹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, the Netherlands.
⁶⁰ Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
⁶¹ Schools of Nursing and Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁶² Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶³ Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
⁶⁴ Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands; Molecular and Experimental Cardiology Group, Academic Medical Centre, 1105 AZ Amsterdam, the Netherlands.
⁶⁵ Human Genetics Center and Institute of Molecular Medicine and Division of Epidemiology, University of Texas Health Science Center, Houston, TX 77030, USA.
⁶⁶ Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK; Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK.
⁶⁷ Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶⁸ Departments of Medicine & Psychiatry, Columbia University, New York, NY 10032, USA.
⁶⁹ The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷⁰ Departments of Pharmacotherapy and Translational Research and Community Health and Family Medicine, University of Florida, Gainesville, FL 32610, USA.
⁷¹ Institute of Molecular Medicine and School of Public Health Division of Epidemiology Human Genetics and Environmental Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁷² Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷³ School of Medicine, University of Pittsburgh, PA 15261, USA.
⁷⁴ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; Hannover Unified Biobank, Hannover Medical School, Hannover 30625, Germany.
⁷⁵ Department of Internal Medicine II - Cardiology, University of Ulm Medical Centre, Ulm 89081, Germany.
⁷⁶ Department of Epidemiology and Public Health, Division of Population Health, University College London, Torrington Place, London WC1E 7HB, UK.
⁷⁷ Medical Clinic V, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany; Synlab Academy, Synlab Services GmbH, Mannheim 69214, Germany; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8036, Austria.
⁷⁸ Department of Pathology, University of California San Diego, La Jolla, CA 92037, USA.
⁷⁹ Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
⁸⁰ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55454, USA.
⁸¹ Cardiovascular Institute, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸² Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
⁸³ Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
⁸⁴ Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
⁸⁵ Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland.
⁸⁶ Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK.
⁸⁷ Departments of Epidemiology and Internal Medicine, Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
⁸⁸ Department of Cardiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, 3511 GC Utrecht, the Netherlands; Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
⁸⁹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
⁹⁰ National Heart, Lung and Blood Institute Framingham Heart Study, Framingham, MA 01702, USA.
⁹¹ Department of Medical Genetics, Biomedical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA and Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁹² Center for Population Studies, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA.
⁹³ Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, 3511 GC Utrecht, the Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London WC1E 6BT, UK.
⁹⁴ Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK. Electronic address: p.b.munroe@qmul.ac.uk.
⁹⁵ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: bkeating@mail.med.upenn.edu.

PMID: 24560520
PMCID: PMC3951943
DOI: 10.1016/j.ajhg.2013.12.016

Abstract

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.

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Figures

**Figure 1**
Overview of the Replicated Blood-Pressure-Related Findings from This Meta-analysis for Overlap with the Various Blood-Pressure-Related Traits Abbreviations are as follows: SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; and PP, pulse pressure.

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References

1. Wilson P.W. Established risk factors and coronary artery disease: the Framingham Study. Am. J. Hypertens. 1994;7:7S–12S. - PubMed
1. Lawes C.M.M., Vander Hoorn S., Rodgers A., International Society of Hypertension Global burden of blood-pressure-related disease, 2001. Lancet. 2008;371:1513–1518. - PubMed
1. Levy D., DeStefano A.L., Larson M.G., O’Donnell C.J., Lifton R.P., Gavras H., Cupples L.A., Myers R.H. Evidence for a gene influencing blood pressure on chromosome 17. Genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the framingham heart study. Hypertension. 2000;36:477–483. - PubMed
1. Kupper N., Willemsen G., Riese H., Posthuma D., Boomsma D.I., de Geus E.J. Heritability of daytime ambulatory blood pressure in an extended twin design. Hypertension. 2005;45:80–85. - PubMed
1. Levy D., Ehret G.B., Rice K., Verwoert G.C., Launer L.J., Dehghan A., Glazer N.L., Morrison A.C., Johnson A.D., Aspelund T. Genome-wide association study of blood pressure and hypertension. Nat. Genet. 2009;41:677–687. - PMC - PubMed

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Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci

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Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci

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