The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals
Patricia Munroe, Christopher Newton-Cheh, Andrew Morris and colleagues perform association studies in over 340,000 individuals of European ancestry and identify 66 loci, of which 17 are novel, involved in blood pressure regulation. The risk SNPs are enriched for cis -regulatory elements, particularl...
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| Published in | Nature genetics Vol. 48; no. 10; pp. 1171 - 1184 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York
Nature Publishing Group US
01.10.2016
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Patricia Munroe, Christopher Newton-Cheh, Andrew Morris and colleagues perform association studies in over 340,000 individuals of European ancestry and identify 66 loci, of which 17 are novel, involved in blood pressure regulation. The risk SNPs are enriched for
cis
-regulatory elements, particularly in vascular endothelial cells.
To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure–associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for
cis
-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure–related pathways and highlight tissues beyond the classical renal system in blood pressure regulation. |
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| AbstractList | Patricia Munroe, Christopher Newton-Cheh, Andrew Morris and colleagues perform association studies in over 340,000 individuals of European ancestry and identify 66 loci, of which 17 are novel, involved in blood pressure regulation. The risk SNPs are enriched for
cis
-regulatory elements, particularly in vascular endothelial cells.
To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure–associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for
cis
-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure–related pathways and highlight tissues beyond the classical renal system in blood pressure regulation. To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation. Patricia Munroe, Christopher Newton-Cheh, Andrew Morris and colleagues perform association studies in over 340,000 individuals of European ancestry and identify 66 loci, of which 17 are novel, involved in blood pressure regulation. The risk SNPs are enriched for cis-regulatory elements, particularly in vascular endothelial cells. To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis -regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation. |
| Audience | Academic |
| Author | Döring, Angela Kumari, Meena Mohlke, Karen L Vasan, Ramachandran S Montasser, May E Luan, Jian'an Chung, Ren-Hua Lee, Wen-Jane Stringham, Heather M Sanna, Serena Elosua, Roberto McCarthy, Mark I Markus, Hugh S Fornage, Myriam Amin, Najaf Baldassarre, Damiano O'Reilly, Paul F Swift, Amy J Hveem, Kristian Hicks, Andrew A Munroe, Patricia B Fraser, Ross M Morrison, Alanna C Elliott, Paul Kim, Young Jin Peters, Annette Chang, I-Shou Bis, Joshua C Burnier, Michel Edkins, Sarah Esko, Tonu Rettig, Rainer Sim, Xueling Liang, Kae-Woei Kaakinen, Marika Felix, Janine F Njølstad, Inger Kolovou, Genovefa Parsa, Afshin Cooper, Richard S Bjornsdottir, Gyda Kvaløy, Kirsti Zhu, Xiaofeng Dallongeville, Jean Bouatia-Naji, Nabila Groves, Christopher J Strawbridge, Rona J Kivimaki, Mika Barroso, Inês Narisu, Narisu Loos, Ruth J F Bochud, Murielle Langenberg, Claudia Boerwinkle, Eric Kutalik, Zoltan Rasheed, Asif Voight, Benjamin F Ferrières, Jean Lind, Lars Chambers, John C Gao, He Hughes, Maria F Bovet, Pascal Newton-Cheh, Christopher Kuh, Diana Ferrucci, Luigi Zhao, We |
| AuthorAffiliation | 170 Population Sciences Branch, National Heart Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA 144 Hannover Medical School, Institute for Human Genetics, Carl-Neuberg-Strasse 1, 30625 Hanover, Germany 255 Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, 9711, The Netherlands 89 Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK 119 Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany 177 Center for Evidence-based Healthcare, University of Dresden, Medical Faculty Carl Gustav Carus, Fetscherstrasse 74, 01307 Dresden, Germany 103 Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK 128 Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU Scotland, UK 140 Department of R |
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Carson Street, Torrance, CA 90502, USA – name: 115 Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, 86077 Pozzilli, Italy – name: 239 Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA – name: 88 UMR744 Inserm-Lille2-Institut Pasteur Lille, France – name: 152 Division of Transplantation, Department of Surgery, University of Pennsylvania, PA 19104 USA – name: 257 Department of Medicine, Central Finland Health Care District, Jyväskylä, Finland – name: 110 Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden – name: 60 Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, 3015CN, The Netherlands – name: 94 Department of Immunology, Genetics and Pathology, University of Uppsala, Box 815, Biomerical center, 751 08 Uppsala, Sweden – name: 108 Tropical Metabolism Research Unit, Tropical Medicine Research Institute, University of the West Indies, Mona, Kingston 7, Jamaica – name: 192 National Heart, Lung and Blood Institute, Division of Intramural Research, Bethesda, MD, USA – name: 221 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597 – name: 255 Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, 9711, The Netherlands – name: 206 Center for Non-Communicable Diseases, Karachi, Pakistan – name: 73 Department of Biological Psychology, VU University, Amsterdam, The Netherlands – name: 40 Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA – name: 122 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK – name: 265 Grosshadern, Klinikum, München 81377, Germany – name: 267 Mindich Child health Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA – name: 47 Department of Epidemiology Research, Statens Serum Institut, 2300, Copenhagen, Denmark – name: 141 Department of Neurology, Erasmus MC, University Medical Center Rotterdam, P.O.Box 2040, 3000 CA Rotterdam, The Netherlands – name: 177 Center for Evidence-based Healthcare, University of Dresden, Medical Faculty Carl Gustav Carus, Fetscherstrasse 74, 01307 Dresden, Germany – name: 118 Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA – name: 20 Department of Odontology, Umeå University, Sweden – name: 183 Department of Twin Research and Genetic Epidemiology, King's College London, London, UK – name: 164 Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland – name: 75 The Barts Heart Centre, William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK – name: 209 Department of Biostatistics, University of Washington, Seattle, WA, USA – name: 160 Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland – name: 114 EPIMED Research Centre - 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Epidemiology and Public Health, UCL, London, WC1E 6BT, UK – name: 107 Institute of Molecular Medicine, University of Texas Health Science Center at Houston, TX, USA – name: 250 Department of Biostatistics and Epidemiology, University of Pennsylvania, USA – name: 163 Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio Campus, Finland – name: 58 HudsonAlpha Institute for Biotechnology, Huntsville, AL 35086, USA – name: 266 The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA – name: 269 Department of Biostatistics, University of Liverpool, Liverpool L69 3GA, UK – name: 14 William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK – name: 4 Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Ave. East, Boston, MA 02215, USA – name: 61 Uppsala University, Department of Medical Sciences, SE-75185 Uppsala, Sweden – name: 64 INSERM Centre for Research in Epidemiology and Population Health, U1018, Villejuif, France University Paris-Sud, URMS 1018, Villejuif, France – name: 226 Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, 21224, USA – name: 95 Science for Life Laboratory, University of Uppsala, Box 815, Biomerical center, 751 08 Uppsala, Sweden – name: 224 Department of Haematology, University of Cambridge, Cambridge, UK – name: 36 Department of Epidemiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands – name: 78 Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex UB1 3EU, UK – name: 218 Munich Heart Alliance, Germany – name: 132 Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland – name: 62 Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy – name: 136 HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, 7600 Levanger, Norway – name: 161 Swiss Institute of Bioinformatics, Lausanne, Switzerland – name: 48 National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA – name: 138 Cardiovascular Genetics Division, University of Utah School of Medicine, Salt Lake City, Utah, USA – name: 241 Department of Epidemiology and Public Health, EA3430, University of Strasbourg, Strasbourg, France – name: 210 University of Ottawa Heart Institute, Cardiovascular Research Methods Centre Ontario, Canada – name: 102 Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden – name: 207 Department of Nutrition, Harvard School of Public Health, Boston, MA, USA |
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Groningen, University Medical Center Groningen, Department of Psychiatry, Leiden University Medical Centre – sequence: 211 givenname: Jacques surname: Rossouw fullname: Rossouw, Jacques organization: Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute – sequence: 214 givenname: Jouko surname: Saramies fullname: Saramies, Jouko organization: South Karelia Central Hospital – sequence: 218 givenname: Young-Ah surname: Shin fullname: Shin, Young-Ah organization: Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex – sequence: 225 givenname: Alice V orcidid: 0000-0002-4961-165X surname: Stanton fullname: Stanton, Alice V organization: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland – sequence: 228 givenname: Johan surname: Sundstrom fullname: Sundstrom, Johan organization: Department of Medical Sciences, Uppsala University – sequence: 230 givenname: Ann-Christine surname: Syvänen fullname: Syvänen, Ann-Christine organization: Department of Medical Sciences, Uppsala University – sequence: 233 givenname: Kirill V orcidid: 0000-0001-7799-4670 surname: Tarasov fullname: Tarasov, Kirill V organization: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, US National Institutes of Health – sequence: 235 givenname: Unnur surname: Thorsteinsdottir fullname: Thorsteinsdottir, Unnur organization: deCODE Genetics/Amgen, Inc., Faculty of Medicine, University of Iceland – sequence: 238 givenname: Andre G surname: Uitterlinden fullname: Uitterlinden, Andre G organization: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Department of Internal Medicine, Erasmus MC – sequence: 240 givenname: Ahmad orcidid: 0000-0001-9048-3795 surname: Vaez fullname: Vaez, Ahmad organization: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences – sequence: 243 givenname: Erik P A surname: van Iperen fullname: van Iperen, Erik P A organization: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Durrer Center for Cardiogenetic Research, ICIN–Netherlands Heart Institute – sequence: 244 givenname: Ramachandran S surname: Vasan fullname: Vasan, Ramachandran S organization: National Heart, Lung, and Blood Institute's Framingham Heart Study, Department of Medicine, Section of Preventive Medicine, Boston University School of Medicine, Department of Medicine, Cardiology, Boston University School of Medicine – sequence: 245 givenname: Germaine C surname: Verwoert fullname: Verwoert, Germaine C organization: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam – sequence: 251 givenname: Louise V orcidid: 0000-0003-4951-1867 surname: Wain fullname: Wain, Louise V organization: Department of Health Sciences, University of Leicester – sequence: 253 givenname: Hugh surname: Watkins fullname: Watkins, Hugh organization: Wellcome Trust Centre for Human Genetics, University of Oxford, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford – sequence: 255 givenname: Harm-Jan orcidid: 0000-0001-7038-567X surname: Westra fullname: Westra, Harm-Jan organization: University of Groningen, University Medical Center Groningen – sequence: 256 givenname: Rainford surname: Wilks fullname: Wilks, Rainford organization: Epidemiology Research Unit, Tropical Medicine Research Institute, University of the West Indies, Mona, Kingston, Jamaica – sequence: 257 givenname: Tom surname: Wilsgaard fullname: Wilsgaard, Tom organization: Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Department of Clinical Medicine, Faculty of Health Sciences, University of Tromsø – sequence: 260 givenname: Tsun-Po surname: Yang fullname: Yang, Tsun-Po organization: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, MRC Cancer Unit, University of Cambridge – sequence: 262 givenname: Loic surname: Yengo fullname: Yengo, Loic organization: European Genomic Institute for Diabetes (EGID), CNRS UMR 8199, Lille Pasteur Institute, Lille 2 University – sequence: 266 givenname: Pascal orcidid: 0000-0002-0242-4259 surname: Bovet fullname: Bovet, Pascal organization: Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Ministry of Health – sequence: 267 givenname: Richard S surname: Cooper fullname: Cooper, Richard S organization: Department of Public Health Sciences, Loyola University Chicago Stritch School of Medicine – sequence: 271 givenname: Paul orcidid: 0000-0002-7511-5684 surname: Elliott fullname: Elliott, Paul organization: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London – sequence: 273 givenname: Cristen J orcidid: 0000-0001-5645-4966 surname: Willer fullname: Willer, Cristen J organization: Department of Computational Medicine and Bioinformatics, University of Michigan, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Department of Human Genetics, University of Michigan – sequence: 280 givenname: Lars surname: Lind fullname: Lind, Lars organization: Department of Medical Sciences, Uppsala University – sequence: 281 givenname: Themistocles L surname: Assimes fullname: Assimes, Themistocles L organization: Department of Medicine, Stanford University School of Medicine – sequence: 285 givenname: Harold surname: Snieder fullname: Snieder, Harold organization: Department of Epidemiology, University of Groningen, University Medical Center Groningen – sequence: 287 givenname: Olle surname: Melander fullname: Melander, Olle organization: Department of Internal Medicine, University of Lund – sequence: 288 givenname: Markku surname: Laakso fullname: Laakso, Markku organization: Department of Medicine, University of Eastern Finland and Kuopio University Hospital – sequence: 290 givenname: Rainer surname: Rauramaa fullname: Rauramaa, Rainer organization: Kuopio Research Institute of Exercise Medicine, Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital – sequence: 292 givenname: Erik surname: Ingelsson fullname: Ingelsson, Erik organization: Department of Medicine, Stanford University School of Medicine, Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University – sequence: 294 givenname: Kristian surname: Hveem fullname: Hveem, Kristian organization: Department of Public Health and General Practice, HUNT Research Centre, Norwegian University of Science and Technology – sequence: 297 givenname: Meena surname: Kumari fullname: Kumari, Meena organization: Department of Epidemiology and Public Health, Genetic Epidemiology Group, University College London – sequence: 300 givenname: Jerome I surname: Rotter fullname: Rotter, Jerome I organization: Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA Medical Center, Institute for Translational Genomics and Population Sciences – sequence: 303 givenname: Edward G surname: Lakatta fullname: Lakatta, Edward G organization: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, US National Institutes of Health – sequence: 308 givenname: Colin N A surname: Palmer fullname: Palmer, Colin N A organization: Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School – sequence: 312 givenname: Aravinda surname: Chakravarti fullname: Chakravarti, Aravinda organization: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine – sequence: 313 givenname: Panos orcidid: 0000-0001-9251-070X surname: Deloukas fullname: Deloukas, Panos organization: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27618452$$D View this record in MEDLINE/PubMed https://hal.inrae.fr/hal-02639685$$DView record in HAL https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-127952$$DView record from Swedish Publication Index https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-306252$$DView record from Swedish Publication Index https://lup.lub.lu.se/record/9b0414b3-9f70-45d7-b5ac-80634646e6e5$$DView record from Swedish Publication Index http://kipublications.ki.se/Default.aspx?queryparsed=id:134294670$$DView record from Swedish Publication Index |
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| Snippet | Patricia Munroe, Christopher Newton-Cheh, Andrew Morris and colleagues perform association studies in over 340,000 individuals of European ancestry and... To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays... To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays... |
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| SubjectTerms | 45/43 631/208/205/2138 692/699/75/243 Agriculture Analysis Animal Genetics and Genomics Asian People - genetics Basic Medicine Biomedicine Black People - genetics Blood pressure Blood Pressure - genetics Blood pressure regulation Cancer Research Cells, Cultured Consortia Gene Function Genealogy Genetic aspects Genetics Genome-Wide Association Study Genomes Genomics Genotypes Human Genetics Humans Hypertension - genetics Hypertension - pathology Hypotheses Kardiologi Klinisk medicin Life Sciences Medical and Health Sciences Medical Genetics Medical schools Medicin och hälsovetenskap Medicinsk genetik Medicinska och farmaceutiska grundvetenskaper Meta-analysis Microarray Analysis Polymorphism, Single Nucleotide Studies |
| Title | The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals |
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