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Meta-Analysis
. 2016 Oct;48(10):1171-1184.
doi: 10.1038/ng.3667. Epub 2016 Sep 12.

The Genetics of Blood Pressure Regulation and Its Target Organs From Association Studies in 342,415 Individuals

Georg B Ehret #  1   2 Teresa Ferreira #  3 Daniel I Chasman  4   5 Anne U Jackson  6   7 Ellen M Schmidt  8 Toby Johnson  9   10 Gudmar Thorleifsson  11 Jian'an Luan  12 Lousie A Donnelly  13 Stavroula Kanoni  14 Ann-Kristin Petersen  15 Vasyl Pihur  1 Rona J Strawbridge  16   17 Dmitry Shungin  18   19   20 Maria F Hughes  21 Osorio Meirelles  22 Marika Kaakinen  23 Nabila Bouatia-Naji  24   25 Kati Kristiansson  26   27 Sonia Shah  28 Marcus E Kleber  29 Xiuqing Guo  30 Leo-Pekka Lyytikäinen  31   32 Cristiano Fava  33   34 Niclas Eriksson  35 Ilja M Nolte  36 Patrik K Magnusson  37 Elias L Salfati  38 Loukianos S Rallidis  39 Elizabeth Theusch  40 Andrew J P Smith  41 Lasse Folkersen  16 Kate Witkowska  9   42 Tune H Pers  43   44   45   46   47 Roby Joehanes  48 Stuart K Kim  49 Lazaros Lataniotis  14 Rick Jansen  50 Andrew D Johnson  48   51 Helen Warren  9   42 Young Jin Kim  52 Wei Zhao  53 Ying Wu  54 Bamidele O Tayo  55 Murielle Bochud  56 CHARGE-EchoGen consortiumCHARGE-HF consortiumWellcome Trust Case Control ConsortiumDevin Absher  57 Linda S Adair  58 Najaf Amin  59 Dan E Arking  1 Tomas Axelsson  60 Damiano Baldassarre  61   62 Beverley Balkau  63 Stefania Bandinelli  64 Michael R Barnes  14   42 Inês Barroso  65   66   67 Stephen Bevan  68 Joshua C Bis  69 Gyda Bjornsdottir  11 Michael Boehnke  6   7 Eric Boerwinkle  70 Lori L Bonnycastle  71 Dorret I Boomsma  72 Stefan R Bornstein  73 Morris J Brown  74 Michel Burnier  75 Claudia P Cabrera  9   42 John C Chambers  76   77   78 I-Shou Chang  79 Ching-Yu Cheng  80   81   82 Peter S Chines  71 Ren-Hua Chung  83 Francis S Collins  71 John M Connell  84 Angela Döring  85   86 Jean Dallongeville  87 John Danesh  88   65   89 Ulf de Faire  90 Graciela Delgado  29 Anna F Dominiczak  91 Alex S F Doney  13 Fotios Drenos  41 Sarah Edkins  65 John D Eicher  48   51 Roberto Elosua  92 Stefan Enroth  93   94 Jeanette Erdmann  95   96 Per Eriksson  16 Tonu Esko  97   98   99 Evangelos Evangelou  76   100 Alun Evans  21 Tove Fall  101 Martin Farrall  3   102 Janine F Felix  103 Jean Ferrières  104 Luigi Ferrucci  105 Myriam Fornage  106 Terrence Forrester  107 Nora Franceschini  108 Oscar H Franco Duran  103 Anders Franco-Cereceda  100 Ross M Fraser  109   110 Santhi K Ganesh  111 He Gao  76 Karl Gertow  16   17 Francesco Gianfagna  112   113 Bruna Gigante  90 Franco Giulianini  4 Anuj Goel  3   102 Alison H Goodall  114   115 Mark O Goodarzi  116 Mathias Gorski  117   118 Jürgen Gräßler  119 Christopher Groves  120 Vilmundur Gudnason  121   122 Ulf Gyllensten  93   94 Göran Hallmans  18 Anna-Liisa Hartikainen  123   124 Maija Hassinen  125 Aki S Havulinna  26 Caroline Hayward  126 Serge Hercberg  127 Karl-Heinz Herzig  128   129   130 Andrew A Hicks  131 Aroon D Hingorani  28 Joel N Hirschhorn  43   44   45   132 Albert Hofman  103   133 Jostein Holmen  134 Oddgeir Lingaas Holmen  134   135 Jouke-Jan Hottenga  72 Phil Howard  41 Chao A Hsiung  83 Steven C Hunt  136   137 M Arfan Ikram  103   138   139 Thomas Illig  140   141   142 Carlos Iribarren  143 Richard A Jensen  70   144 Mika Kähönen  145 Hyun Kang  6   7 Sekar Kathiresan  146   147   148   45   149 Brendan J Keating  150   151 Kay-Tee Khaw  152 Yun Kyoung Kim  52 Eric Kim  153 Mika Kivimaki  28 Norman Klopp  140   141 Genovefa Kolovou  154 Pirjo Komulainen  125 Jaspal S Kooner  155   77   78 Gulum Kosova  147   146   99 Ronald M Krauss  156 Diana Kuh  157 Zoltan Kutalik  158   159 Johanna Kuusisto  160 Kirsti Kvaløy  134 Timo A Lakka  161   125   162 Nanette R Lee  163   164 I-Te Lee  165   166 Wen-Jane Lee  167 Daniel Levy  48   168 Xiaohui Li  30 Kae-Woei Liang  169   170 Honghuang Lin  171   48 Li Lin  2 Jaana Lindström  26 Stéphane Lobbens  172   173   174 Satu Männistö  26 Gabriele Müller  175 Martina Müller-Nurasyid  15   176   177 François Mach  2 Hugh S Markus  178 Eirini Marouli  14   179 Mark I McCarthy  120 Colin A McKenzie  107 Pierre Meneton  180 Cristina Menni  181 Andres Metspalu  97 Vladan Mijatovic  182 Leena Moilanen  183   184 May E Montasser  185 Andrew D Morris  13 Alanna C Morrison  186 Antonella Mulas  187 Ramaiah Nagaraja  22 Narisu Narisu  71 Kjell Nikus  188   189 Christopher J O'Donnell  190   48   149 Paul F O'Reilly  191 Ken K Ong  12 Fred Paccaud  56 Cameron D Palmer  192   193   45 Afshin Parsa  185 Nancy L Pedersen  37 Brenda W Penninx  194   195   196 Markus Perola  26   27   97 Annette Peters  86 Neil Poulter  197 Peter P Pramstaller  131   198   199 Bruce M Psaty  69   200   201   202 Thomas Quertermous  38 Dabeeru C Rao  203 Asif Rasheed  204 N William N W R Rayner  120   3   65 Frida Renström  19   205   18 Rainer Rettig  206 Kenneth M Rice  207 Robert Roberts  208   209 Lynda M Rose  4 Jacques Rossouw  210 Nilesh J Samani  114   211 Serena Sanna  187 Jouko Saramies  212 Heribert Schunkert  213   214   215   216 Sylvain Sebert  217   129   162 Wayne H-H Sheu  165   166   218 Young-Ah Shin  52 Xueling Sim  6   7   219 Johannes H Smit  194 Albert V Smith  121   122 Maria X Sosa  1 Tim D Spector  181 Alena Stančáková  220 Alice Stanton  221 Kathleen E Stirrups  14   222 Heather M Stringham  6   7 Johan Sundstrom  60 Amy J Swift  71 Ann-Christine Syvänen  60 E-Shyong Tai  223   81   219 Toshiko Tanaka  105 Kirill V Tarasov  224 Alexander Teumer  225 Unnur Thorsteinsdottir  11   122 Martin D Tobin  226 Elena Tremoli  61   62 Andre G Uitterlinden  103   227 Matti Uusitupa  228   229 Ahmad Vaez  36   230 Dhananjay Vaidya  231 Cornelia M van Duijn  103   232 Erik P A van Iperen  233   234 Ramachandran S Vasan  48   235   236 Germaine C Verwoert  103 Jarmo Virtamo  26 Veronique Vitart  126 Benjamin F Voight  45   237 Peter Vollenweider  238 Aline Wagner  239 Louise V Wain  226 Nicholas J Wareham  12 Hugh Watkins  3   102 Alan B Weder  240 Harm-Jan Westra  241 Rainford Wilks  242 Tom Wilsgaard  243   244 James F Wilson  109   126 Tien Y Wong  80   81   82 Tsun-Po Yang  14   245 Jie Yao  30 Loic Yengo  172   173   174 Weihua Zhang  76   77 Jing Hua Zhao  12 Xiaofeng Zhu  246 Pascal Bovet  247   56 Richard S Cooper  55 Karen L Mohlke  54 Danish Saleheen  248   204 Jong-Young Lee  52 Paul Elliott  76   249 Hinco J Gierman  49   250 Cristen J Willer  8   251   252 Lude Franke  253 G Kees Hovingh  254 Kent D Taylor  30 George Dedoussis  179 Peter Sever  197 Andrew Wong  157 Lars Lind  60 Themistocles L Assimes  38 Inger Njølstad  243   244 Peter Eh Schwarz  73 Claudia Langenberg  12 Harold Snieder  36 Mark J Caulfield  9   42 Olle Melander  33 Markku Laakso  160 Juha Saltevo  255 Rainer Rauramaa  125   162 Jaakko Tuomilehto  26   256   257   258 Erik Ingelsson  101   3 Terho Lehtimäki  31   32 Kristian Hveem  134 Walter Palmas  259 Winfried März  260   261 Meena Kumari  28 Veikko Salomaa  26 Yii-Der I Chen  30 Jerome I Rotter  30 Philippe Froguel  172   173   174   23 Marjo-Riitta Jarvelin  217   129   262   249 Edward G Lakatta  224 Kari Kuulasmaa  26 Paul W Franks  19   205   18 Anders Hamsten  16   17 H-Erich Wichmann  85   177   263 Colin N A Palmer  13 Kari Stefansson  11   122 Paul M Ridker  4   5 Ruth J F Loos  12   264   265 Aravinda Chakravarti  1 Panos Deloukas  14   266 Andrew P Morris  267   3 Christopher Newton-Cheh  146   147   45   99 Patricia B Munroe  9   42
Affiliations
Free PMC article
Meta-Analysis

The Genetics of Blood Pressure Regulation and Its Target Organs From Association Studies in 342,415 Individuals

Georg B Ehret et al. Nat Genet. .
Free PMC article

Abstract

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.

Figures

Figure 1
Figure 1. Manhattan plots for SBP and DBP from the stage 4 Cardio-MetaboChip-wide meta-analysis
P values (expressed as -log10P) are plotted by physical genomic position labeled by chromosome. SNPs in new loci (3.5MB window around the index SNP), identified in this study, are labeled in dark red (SBP) or dark blue (DBP); SNPs in previously known loci are labeled in orange (SBP) or light blue (DBP). The locus names are indicated. The grey crosses indicate genomic positions at which the y-axis was truncated (SNPs with P < 10−15).
Figure 2
Figure 2. Enrichment of DNAse hypersensitive sites among BP loci in different cell-types
Enrichment analyses of SBP or DBP associated loci according to discovery P value using narrow peaks (panel A) or broad peaks (panel B). SNPs were selected according to different P value cutoffs (x-axis) and a fold enrichment of overlap with DNAse hypersensitive sites compared to unrelated GWAS SNPs was calculated (y-axis) (see Supplementary Note). The 12 endothelial cell-lines are indicated in color and for each endothelial cell-type the rank using the 10−14 P value cutoff is indicated. EC denotes endothelial cells.

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