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Am J Hum Genet. 2014 Mar 6;94(3):349-60. doi: 10.1016/j.ajhg.2013.12.016. Epub 2014 Feb 20.

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

Tragante V1, Barnes MR2, Ganesh SK3, Lanktree MB4, Guo W5, Franceschini N6, Smith EN7, Johnson T8, Holmes MV9, Padmanabhan S10, Karczewski KJ11, Almoguera B12, Barnard J13, Baumert J14, Chang YP15, Elbers CC16, Farrall M17, Fischer ME18, Gaunt TR19, Gho JM20, Gieger C21, Goel A17, Gong Y22, Isaacs A23, Kleber ME24, Mateo Leach I25, McDonough CW22, Meijs MF20, Melander O26, Nelson CP27, Nolte IM28, Pankratz N29, Price TS30, Shaffer J31, Shah S32, Tomaszewski M33, van der Most PJ28, Van Iperen EP34, Vonk JM28, Witkowska K8, Wong CO8, Zhang L13, Beitelshees AL35, Berenson GS36, Bhatt DL37, Brown M38, Burt A39, Cooper-DeHoff RM22, Connell JM40, Cruickshanks KJ41, Curtis SP42, Davey-Smith G19, Delles C43, Gansevoort RT44, Guo X45, Haiqing S35, Hastie CE43, Hofker MH46, Hovingh GK47, Kim DS48, Kirkland SA49, Klein BE18, Klein R18, Li YR12, Maiwald S47, Newton-Cheh C50, O'Brien ET51, Onland-Moret NC16, Palmas W31, Parsa A35, Penninx BW52, Pettinger M53, Vasan RS54, Ranchalis JE39, M Ridker P55, Rose LM56, Sever P57, Shimbo D31, Steele L9, Stolk RP28, Thorand B14, Trip MD58, van Duijn CM23, Verschuren WM59, Wijmenga C60, Wyatt S61, Young JH62, Zwinderman AH63, Bezzina CR64, Boerwinkle E65, Casas JP66, Caulfield MJ8, Chakravarti A67, Chasman DI55, Davidson KW68, Doevendans PA20, Dominiczak AF10, FitzGerald GA69, Gums JG70, Fornage M71, Hakonarson H72, Halder I73, Hillege HL25, Illig T74, Jarvik GP57, Johnson JA22, Kastelein JJ47, Koenig W75, Kumari M76, März W77, Murray SS78, O'Connell JR35, Oldehinkel AJ79, Pankow JS80, Rader DJ81, Redline S82, Reilly MP81, Schadt EE83, Kottke-Marchant K84, Snieder H28, Snyder M11, Stanton AV85, Tobin MD86, Uitterlinden AG87, van der Harst P88, van der Schouw YT89, Samani NJ27, Watkins H17, Johnson AD90, Reiner AP53, Zhu X5, de Bakker PI91, Levy D92, Asselbergs FW93, Munroe PB94, Keating BJ95.

Author information

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.

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.

PMID:
24560520
PMCID:
PMC3951943
DOI:
10.1016/j.ajhg.2013.12.016
[Indexed for MEDLINE]
Free PMC Article

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