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Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.
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MedLine Citation:
PMID:  21909110     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
Authors:
Louise V Wain; Germaine C Verwoert; Paul F O'Reilly; Gang Shi; Toby Johnson; Andrew D Johnson; Murielle Bochud; Kenneth M Rice; Peter Henneman; Albert V Smith; Georg B Ehret; Najaf Amin; Martin G Larson; Vincent Mooser; David Hadley; Marcus Dörr; Joshua C Bis; Thor Aspelund; Tõnu Esko; A Cecile J W Janssens; Jing Hua Zhao; Simon Heath; Maris Laan; Jingyuan Fu; Giorgio Pistis; Jian'an Luan; Pankaj Arora; Gavin Lucas; Nicola Pirastu; Irene Pichler; Anne U Jackson; Rebecca J Webster; Feng Zhang; John F Peden; Helena Schmidt; Toshiko Tanaka; Harry Campbell; Wilmar Igl; Yuri Milaneschi; Jouke-Jan Hottenga; Veronique Vitart; Daniel I Chasman; Stella Trompet; Jennifer L Bragg-Gresham; Behrooz Z Alizadeh; John C Chambers; Xiuqing Guo; Terho Lehtimäki; Brigitte Kühnel; Lorna M Lopez; Ozren Polašek; Mladen Boban; Christopher P Nelson; Alanna C Morrison; Vasyl Pihur; Santhi K Ganesh; Albert Hofman; Suman Kundu; Francesco U S Mattace-Raso; Fernando Rivadeneira; Eric J G Sijbrands; Andre G Uitterlinden; Shih-Jen Hwang; Ramachandran S Vasan; Thomas J Wang; Sven Bergmann; Peter Vollenweider; Gérard Waeber; Jaana Laitinen; Anneli Pouta; Paavo Zitting; Wendy L McArdle; Heyo K Kroemer; Uwe Völker; Henry Völzke; Nicole L Glazer; Kent D Taylor; Tamara B Harris; Helene Alavere; Toomas Haller; Aime Keis; Mari-Liis Tammesoo; Yurii Aulchenko; Inês Barroso; Kay-Tee Khaw; Pilar Galan; Serge Hercberg; Mark Lathrop; Susana Eyheramendy; Elin Org; Siim Sõber; Xiaowen Lu; Ilja M Nolte; Brenda W Penninx; Tanguy Corre; Corrado Masciullo; Cinzia Sala; Leif Groop; Benjamin F Voight; Olle Melander; Christopher J O'Donnell; Veikko Salomaa; Adamo Pio d'Adamo; Antonella Fabretto; Flavio Faletra; Sheila Ulivi; Fabiola M Del Greco; Maurizio Facheris; Francis S Collins; Richard N Bergman; John P Beilby; Joseph Hung; A William Musk; Massimo Mangino; So-Youn Shin; Nicole Soranzo; Hugh Watkins; Anuj Goel; Anders Hamsten; Pierre Gider; Marisa Loitfelder; Marion Zeginigg; Dena Hernandez; Samer S Najjar; Pau Navarro; Sarah H Wild; Anna Maria Corsi; Andrew Singleton; Eco J C de Geus; Gonneke Willemsen; Alex N Parker; Lynda M Rose; Brendan Buckley; David Stott; Marco Orru; Manuela Uda; ; Melanie M van der Klauw; Weihua Zhang; Xinzhong Li; James Scott; Yii-Der Ida Chen; Gregory L Burke; Mika Kähönen; Jorma Viikari; Angela Döring; Thomas Meitinger; Gail Davies; John M Starr; Valur Emilsson; Andrew Plump; Jan H Lindeman; Peter A C 't Hoen; Inke R König; ; Janine F Felix; Robert Clarke; Jemma C Hopewell; Halit Ongen; Monique Breteler; Stéphanie Debette; Anita L Destefano; Myriam Fornage; ; Gary F Mitchell; ; Nicholas L Smith; ; Hilma Holm; Kari Stefansson; Gudmar Thorleifsson; Unnur Thorsteinsdottir; ; ; ; Nilesh J Samani; Michael Preuss; Igor Rudan; Caroline Hayward; Ian J Deary; H-Erich Wichmann; Olli T Raitakari; Walter Palmas; Jaspal S Kooner; Ronald P Stolk; J Wouter Jukema; Alan F Wright; Dorret I Boomsma; Stefania Bandinelli; Ulf B Gyllensten; James F Wilson; Luigi Ferrucci; Reinhold Schmidt; Martin Farrall; Tim D Spector; Lyle J Palmer; Jaakko Tuomilehto; Arne Pfeufer; Paolo Gasparini; David Siscovick; David Altshuler; Ruth J F Loos; Daniela Toniolo; Harold Snieder; Christian Gieger; Pierre Meneton; Nicholas J Wareham; Ben A Oostra; Andres Metspalu; Lenore Launer; Rainer Rettig; David P Strachan; Jacques S Beckmann; Jacqueline C M Witteman; Jeanette Erdmann; Ko Willems van Dijk; Eric Boerwinkle; Michael Boehnke; Paul M Ridker; Marjo-Riitta Jarvelin; Aravinda Chakravarti; Goncalo R Abecasis; Vilmundur Gudnason; Christopher Newton-Cheh; Daniel Levy; Patricia B Munroe; Bruce M Psaty; Mark J Caulfield; Dabeeru C Rao; Martin D Tobin; Paul Elliott; Cornelia M van Duijn
Publication Detail:
Type:  Journal Article; Meta-Analysis; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-09-11
Journal Detail:
Title:  Nature genetics     Volume:  43     ISSN:  1546-1718     ISO Abbreviation:  Nat. Genet.     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-09-29     Completed Date:  2011-11-21     Revised Date:  2014-06-09    
Medline Journal Info:
Nlm Unique ID:  9216904     Medline TA:  Nat Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1005-11     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Arteries / metabolism
Blood Pressure / genetics*
Case-Control Studies
Follow-Up Studies
Genetic Loci
Genome-Wide Association Study*
Humans
Hypertension / genetics
Linkage Disequilibrium
Polymorphism, Single Nucleotide
Grant Support
ID/Acronym/Agency:
090532//Wellcome Trust; 263 MD9164 13/MD/NIMHD NIH HHS; CZB/4/710//Chief Scientist Office; G0401527//Medical Research Council; G0601966//Medical Research Council; G0700931//Medical Research Council; G0701863//Medical Research Council; G0801056//Medical Research Council; G0902313//Medical Research Council; G1000143//Medical Research Council; G9521010//Medical Research Council; K23 HL080025/HL/NHLBI NIH HHS; MC_PC_U127561128//Medical Research Council; MC_U106179471//Medical Research Council; MC_U106188470//Medical Research Council; MC_U127561128//Medical Research Council; MC_U127592696//Medical Research Council; N01 AG012109/AG/NIA NIH HHS; N01 HC025195/HC/NHLBI NIH HHS; N01 HC055015/HC/NHLBI NIH HHS; N01 HC085079/HC/NHLBI NIH HHS; N01 HC095159/HC/NHLBI NIH HHS; R01 HL043851/HL/NHLBI NIH HHS; R01 HL086694/HL/NHLBI NIH HHS; R01 HL087647/HL/NHLBI NIH HHS; R01 HL105756/HL/NHLBI NIH HHS; U10 HL054512/HL/NHLBI NIH HHS; Z01 HG000024-13/HG/NHGRI NIH HHS
Investigator
Investigator/Affiliation:
Carmel M McEniery / ; Ian B Wilkinson / ; John R Cockcroft / ; Kevin M O'Shaughnessy / ; Stephen J Newhouse / ; Yasmin / ; Albert V Smith / ; Gudny Eiriksdottir / ; Lenore J Launer / ; Sigurdur Sigurdsson / ; Thor Aspelund / ; Vilmundur Gudnason / ; Dirk De Bacquer / ; Ernst R Rietzschel / ; Guy G De Backer / ; Luc Van Bortel / ; Marc L De Buyzere / ; Patrick Segers / ; Sofie Bekaert / ; Thierry C Gillebert / ; Tim De Meyer / ; Luigi Ferrucci / ; Toshiko Tanaka / ; Andrew D Johnson / ; Daniel Levy / ; Emelia J Benjamin / ; Gary F Mitchell / ; Joseph A Vita / ; Martin G Larson / ; Naomi M Hamburg / ; Ramachandran S Vasan / ; Aaron Isaacs / ; Anna F C Schut / ; Ben A Oostra / ; Cornelia M van Duijn / ; Marie Josee E van Rijn / ; Mark P Sie / ; Anne B Newman / ; David M Herrington / ; Jeanette S Andrews / ; Jingzhong Ding / ; Kim C Sutton-Tyrrell / ; Tamara B Harris / ; Timothy D Howard / ; Yongmei Liu / ; Afshin Parsa / ; Alan R Shuldiner / ; Patrick F McArdle / ; Quince Gibson / ; Wendy S Post / ; Abbas Dehghan / ; Albert Hofman / ; André G Uitterlinden / ; Eric J G Sijbrands / ; Fernando Rivadeneira / ; Francesco U S Mattace-Raso / ; Germaine C Verwoert / ; Jacqueline C M Witteman / ; Angelo Scuteri / ; Edward G Lakatta / ; Elizabeth Jewell / ; Gonçalo R Abecasis / ; Kirill V Tarasov / ; Manuela Uda / ; Samer S Najjar / ; Serena Sanna / ; Tony Attwood / ; Stephanie Belz / ; Peter Braund / ; François Cambien / ; Jason Cooper / ; Abi Crisp-Hihn / ; Panos Deloukas / ; Nicola Foad / ; Jeanette Eardman / ; Alison H Goodall / ; Jay Gracey / ; Emma Gray / ; Stefanie Gulde / ; Rhian Gwilliams / ; Susanne Heimerl / ; Christian Hengstenberg / ; Jennifer Jolley / ; Unni Krishnan / ; Patrick Linsel-Nitschke / ; Heather Lloyd-Jones / ; Ingrid Lugauer / ; Per Lundmark / ; Seraya Maouche / ; Jasbir S Moore / ; David Muir / ; Elizabeth Murray / ; Chris P Nelson / ; Jessica Neudert / ; David Niblett / ; Karen O'Leary / ; Willem H Ouwehand / ; Helen Pollard / ; Angela Rankin / ; Catherine M Rice / ; Hendrik Sager / ; Nilesh J Samani / ; Jennifer Sambrook / ; Gerd Schmitz / ; Michael Scholz / ; Laura Schroeder / ; Heribert Schunkert / ; Ann-Christine Syvannen / ; Chris Wallace / ; Sekar Kathiresan / ; Muredach P Reilly / ; Nilesh J Samani / ; Heribert Schunkert / ; Jeanette Erdmann / ; Themistocles L Assimes / ; Eric Boerwinkle / ; Jeanette Erdmann / ; Alistair Hall / ; Christian Hengstenberg / ; Sekar Kathiresan / ; Inke R König / ; Reijo Laaksonen / ; Ruth McPherson / ; Muredach P Reilly / ; Nilesh J Samani / ; Heribert Schunkert / ; John R Thompson / ; Unnur Thorsteinsdottir / ; Andreas Ziegler / ; Inke R König / ; John R Thompson / ; Devin Absher / ; Li Chen / ; L Adrienne Cupples / ; Eran Halperin / ; Mingyao Li / ; Kiran Musunuru / ; Michael Preuss / ; Arne Schillert / ; Gudmar Thorleifsson / ; Benjamin F Voight / ; George A Wells / ; Themistocles L Assime / ; Panos Deloukas / ; Jeanette Erdmann / ; Hilma Holm / ; Sekar Kathiresan / ; Inke R König / ; Ruth McPherson / ; Muredach P Reilly / ; Robert Roberts / ; Nilesh J Samani / ; Heribert Schunkert / ; Alexandre F R Stewart / ; Devin Absher / ; Themistocles L Assimes / ; Stephen Fortmann / ; Alan Go / ; Mark Hlatky / ; Carlos Iribarren / ; Joshua Knowles / ; Richard Myers / ; Thomas Quertermous / ; Steven Sidney / ; Neil Risch / ; Hua Tang / ; Stefan Blankenberg / ; Tanja Zeller / ; Arne Schillert / ; Philipp Wild / ; Andreas Ziegler / ; Renate Schnabel / ; Christoph Sinning / ; Karl Lackner / ; Laurence Tiret / ; Viviane Nicaud / ; Francois Cambien / ; Christoph Bickel / ; Hans J Rupprecht / ; Claire Perret / ; Carole Proust / ; Thomas Münzel / ; Maja Barbalic / ; Joshua Bis / ; Eric Boerwinkle / ; Ida Yii-Der Chen / ; L Adrienne Cupples / ; Abbas Dehghan / ; Serkalem Demissie-Banjaw / ; Aaron Folsom / ; Nicole Glazer / ; Vilmundur Gudnason / ; Tamara Harris / ; Susan Heckbert / ; Daniel Levy / ; Thomas Lumley / ; Kristin Marciante / ; Alanna Morrison / ; Christopher J O' Donnell / ; Bruce M Psaty / ; Kenneth Rice / ; Jerome I Rotter / ; David S Siscovick / ; Nicholas Smith / ; Albert Smith / ; Kent D Taylor / ; Cornelia van Duijn / ; Kelly Volcik / ; Jaqueline Whitteman / ; Vasan Ramachandran / ; Albert Hofman / ; Andre Uitterlinden / ; Solveig Gretarsdottir / ; Jeffrey R Gulcher / ; Hilma Holm / ; Augustine Kong / ; Kari Stefansson / ; Gudmundur Thorgeirsson / ; Karl Andersen / ; Gudmar Thorleifsson / ; Unnur Thorsteinsdottir / ; Jeanette Erdmann / ; Marcus Fischer / ; Anika Grosshennig / ; Christian Hengstenberg / ; Inke R König / ; Wolfgang Lieb / ; Patrick Linsel-Nitschke / ; Michael Preuss / ; Klaus Stark / ; Stefan Schreiber / ; H-Erich Wichmann / ; Andreas Ziegler / ; Heribert Schunkert / ; Zouhair Aherrahrou / ; Petra Bruse / ; Angela Doering / ; Jeanette Erdmann / ; Christian Hengstenberg / ; Thomas Illig / ; Norman Klopp / ; Inke R König / ; Patrick Linsel-Nitschke / ; Christina Loley / ; Anja Medack / ; Christina Meisinger / ; Thomas Meitinger / ; Janja Nahrstedt / ; Annette Peters / ; Michael Preuss / ; Klaus Stark / ; Arnika K Wagner / ; H-Erich Wichmann / ; Christina Willenborg / ; Andreas Ziegler / ; Heribert Schunkert / ; Bernhard O Böhm / ; Harald Dobnig / ; Tanja B Grammer / ; Eran Halperin / ; Michael M Hoffmann / ; Marcus Kleber / ; Reijo Laaksonen / ; Winfried März / ; Andreas Meinitzer / ; Bernhard R Winkelmann / ; Stefan Pilz / ; Wilfried Renner / ; Hubert Scharnagl / ; Tatjana Stojakovic / ; Andreas Tomaschitz / ; Karl Winkler / ; Benjamin F Voight / ; Kiran Musunuru / ; Candace Guiducci / ; Noel Burtt / ; Stacey B Gabriel / ; David S Siscovick / ; Christopher J O'Donnell / ; Roberto Elosua / ; Leena Peltonen / ; Veikko Salomaa / ; Stephen M Schwartz / ; Olle Melander / ; David Altshuler / ; Sekar Kathiresan / ; Alexandre F R Stewart / ; Li Chen / ; Sonny Dandona / ; George A Wells / ; Olga Jarinova / ; Ruth McPherson / ; Robert Roberts / ; Muredach P Reilly / ; Mingyao Li / ; Liming Qu / ; Robert Wilensky / ; William Matthai / ; Hakon H Hakonarson / ; Joe Devaney / ; Mary Susan Burnett / ; Augusto D Pichard / ; Kenneth M Kent / ; Lowell Satler / ; Joseph M Lindsay / ; Ron Waksman / ; Christopher W Knouff / ; Dawn M Waterworth / ; Max C Walker / ; Vincent Mooser / ; Stephen E Epstein / ; Daniel J Rader / ; Nilesh J Samani / ; John R Thompson / ; Peter S Braund / ; Christopher P Nelson / ; Benjamin J Wright / ; Anthony J Balmforth / ; Stephen G Ball / ; Alistair S Hall / ; Nicholas L Smith / ; Janine F Felix / ; Alanna C Morrison / ; Serkalem Demissie / ; Nicole L Glazer / ; Laura R Loehr / ; L Adrienne Cupples / ; Abbas Dehghan / ; Thomas Lumley / ; Wayne D Rosamond / ; Wolfgang Lieb / ; Fernando Rivadeneira / ; Joshua C Bis / ; Aaron R Folsom / ; Emelia Benjamin / ; Yurii S Aulchenko / ; Talin Haritunians / ; David Couper / ; Joanne Murabito / ; Ying A Yang / ; Bruno H Stricker / ; John S Gottdiener / ; Patricia P Chang / ; Thomas J Wang / ; Kenneth M Rice / ; Albert Hofman / ; Susan R Heckbert / ; Ervin R Fox / ; Christopher J O'Donnell / ; Andre G Uitterlinden / ; Jerome I Rotter / ; James T Willerson / ; Daniel Levy / ; Cornelia M van Duijn / ; Bruce M Psaty / ; Jacqueline C M Witteman / ; Eric Boerwinkle / ; Ramachandran S Vasan / ; A Köttgen / ; C Pattaro / ; C A Böger / ; C Fuchsberger / ; M Olden / ; N L Glazer / ; A Parsa / ; X Gao / ; Q Yang / ; A V Smith / ; J R O'Connell / ; M Li / ; H Schmidt / ; T Tanaka / ; A Isaacs / ; S Ketkar / ; S J Hwang / ; A D Johnson / ; A Dehghan / ; A Teumer / ; G Paré / ; E J Atkinson / ; T Zeller / ; K Lohman / ; M C Cornelis / ; N M Probst-Hensch / ; F Kronenberg / ; A Tönjes / ; C Hayward / ; T Aspelund / ; G Eiriksdottir / ; L J Launer / ; T B Harris / ; E Rampersaud / ; B D Mitchell / ; D E Arking / ; E Boerwinkle / ; M Struchalin / ; M Cavalieri / ; A Singleton / ; F Giallauria / ; J Metter / ; I H de Boer / ; T Haritunians / ; T Lumley / ; D Siscovick / ; B M Psaty / ; M C Zillikens / ; B A Oostra / ; M Feitosa / ; M Province / ; M de Andrade / ; S T Turner / ; A Schillert / ; A Ziegler / ; P S Wild / ; R B Schnabel / ; S Wilde / ; T F Munzel / ; T S Leak / ; T Illig / ; N Klopp / ; C Meisinger / ; H E Wichmann / ; W Koenig / ; L Zgaga / ; T Zemunik / ; I Kolcic / ; C Minelli / ; F B Hu / ; A Johansson / ; W Igl / ; G Zaboli / ; S H Wild / ; A F Wright / ; H Campbell / ; D Ellinghaus / ; S Schreiber / ; Y S Aulchenko / ; J F Felix / ; F Rivadeneira / ; A G Uitterlinden / ; A Hofman / ; M Imboden / ; D Nitsch / ; A Brandstätter / ; B Kollerits / ; L Kedenko / ; R Mägi / ; M Stumvoll / ; P Kovacs / ; M Boban / ; S Campbell / ; K Endlich / ; H Völzke / ; H K Kroemer / ; M Nauck / ; U Völker / ; O Polasek / ; V Vitart / ; S Badola / ; A N Parker / ; P M Ridker / ; S L Kardia / ; S Blankenberg / ; Y Liu / ; G C Curhan / ; A Franke / ; T Rochat / ; B Paulweber / ; I Prokopenko / ; W Wang / ; V Gudnason / ; A R Shuldiner / ; J Coresh / ; R Schmidt / ; L Ferrucci / ; M G Shlipak / ; C M van Duijn / ; I Borecki / ; B K Krämer / ; I Rudan / ; U Gyllensten / ; J F Wilson / ; J C Witteman / ; P P Pramstaller / ; Rettig R / ; N Hastie / ; D I Chasman / ; W H Kao / ; I M Heid / ; C S Fox / ; R S Vasan / ; N L Glazer / ; J F Felix / ; W Lieb / ; P S Wild / ; S B Felix / ; N Watzinger / ; M G Larson / ; N L Smith / ; A Dehghan / ; A Grosshennig / ; A Schillert / ; A Teumer / ; R Schmidt / ; S Kathiresan / ; T Lumley / ; Y S Aulchenko / ; I R König / ; T Zeller / ; G Homuth / ; M Struchalin / ; J Aragam / ; J C Bis / ; F Rivadeneira / ; J Erdmann / ; R B Schnabel / ; M Dörr / ; R Zweiker / ; L Lind / ; R J Rodeheffer / ; K H Greiser / ; D Levy / ; T Haritunians / ; J W Deckers / ; J Stritzke / ; K J Lackner / ; U Völker / ; E Ingelsson / ; I Kullo / ; J Haerting / ; C J O'Donnell / ; S R Heckbert / ; B H Stricker / ; A Ziegler / ; T Reffelmann / ; M M Redfield / ; K Werdan / ; G F Mitchell / ; K Rice / ; D K Arnett / ; A Hofman / ; J S Gottdiener / ; A G Uitterlinden / ; T Meitinger / ; M Blettner / ; N Friedrich / ; T J Wang / ; B M Psaty / ; C M van Duijn / ; H E Wichmann / ; T F Munzel / ; H K Kroemer / ; E J Benjamin / ; J I Rotter / ; J C Witteman / ; H Schunkert / ; H Schmidt / ; H Völzke / ; S Blankenberg / ; J C Chambers / ; W Zhang / ; G M Lord / ; P van der Harst / ; D A Lawlor / ; J S Sehmi / ; D P Gale / ; M N Wass / ; K R Ahmadi / ; S J Bakker / ; J Beckmann / ; H J Bilo / ; M Bochud / ; M J Brown / ; M J Caulfield / ; J M Connell / ; H T Cook / ; I Cotlarciuc / ; G Davey Smith / ; R de Silva / ; G Deng / ; O Devuyst / ; L D Dikkeschei / ; N Dimkovic / ; M Dockrell / ; A Dominiczak / ; S Ebrahim / ; T Eggermann / ; M Farrall / ; L Ferrucci / ; J Floege / ; N G Forouhi / ; R T Gansevoort / ; X Han / ; B Hedblad / ; J J Homan van der Heide / ; B G Hepkema / ; M Hernandez-Fuentes / ; E Hypponen / ; T Johnson / ; P E de Jong / ; N Kleefstra / ; V Lagou / ; M Lapsley / ; Y Li / ; R J Loos / ; J Luan / ; K Luttropp / ; C Maréchal / ; O Melander / ; P B Munroe / ; L Nordfors / ; A Parsa / ; L Peltonen / ; B W Penninx / ; E Perucha / ; A Pouta / ; I Prokopenko / ; P J Roderick / ; A Ruokonen / ; N J Samani / ; S Sanna / ; M Schalling / ; D Schlessinger / ; G Schlieper / ; M A Seelen / ; A R Shuldiner / ; M Sjögren / ; J H Smit / ; H Snieder / ; N Soranzo / ; T D Spector / ; P Stenvinkel / ; M J Sternberg / ; R Swaminathan / ; T Tanaka / ; L J Ubink-Veltmaat / ; M Uda / ; P Vollenweider / ; C Wallace / ; D Waterworth / ; K Zerres / ; G Waeber / ; N J Wareham / ; P H Maxwell / ; M I McCarthy / ; M R Jarvelin / ; V Mooser / ; G R Abecasis / ; L Lightstone / ; J Scott / ; G Navis / ; P Elliott / ; J S Kooner /
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Journal Information
Journal ID (nlm-journal-id): 9216904
Journal ID (pubmed-jr-id): 2419
Journal ID (nlm-ta): Nat Genet
Journal ID (iso-abbrev): Nat. Genet.
ISSN: 1061-4036
ISSN: 1546-1718
Article Information
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nihms-submitted publication date: Day: 31 Month: 7 Year: 2012
Electronic publication date: Day: 11 Month: 9 Year: 2011
pmc-release publication date: Day: 18 Month: 9 Year: 2012
Volume: 43 Issue: 10
First Page: 1005 Last Page: 1011
ID: 3445021
PubMed Id: 21909110
DOI: 10.1038/ng.922
ID: nihpa316759

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure
Louise V Wain12180
Germaine C Verwoert34180
Paul F O’Reilly5180
Gang Shi67180
Toby Johnson8180
Andrew D Johnson910
Murielle Bochud1112
Kenneth M Rice13
Peter Henneman14
Albert V Smith1516
Georg B Ehret171819
Najaf Amin20
Martin G Larson921
Vincent Mooser22
David Hadley2324
Marcus Dörr25
Joshua C Bis26
Thor Aspelund1516
Tõnu Esko272829
A Cecile JW Janssens20
Jing Hua Zhao30
Simon Heath31
Maris Laan29
Jingyuan Fu3233
Giorgio Pistis34
Jian’an Luan30
Pankaj Arora35
Gavin Lucas36
Nicola Pirastu37
Irene Pichler38
Anne U Jackson39
Rebecca J Webster40
Feng Zhang41
John F Peden4243
Helena Schmidt44
Toshiko Tanaka45
Harry Campbell46
Wilmar Igl47
Yuri Milaneschi45
Jouke-Jan Hotteng48
Veronique Vitart49
Daniel I Chasman5051
Stella Trompet5253
Jennifer L Bragg-Gresham39
Behrooz Z Alizadeh32
John C Chambers554
Xiuqing Guo55
Terho Lehtimäki56
Brigitte Kühnel57
Lorna M Lopez5859
Ozren Polašek60
Mladen Boban61
Christopher P Nelson62
Alanna C Morrison63
Vasyl Pihur17
Santhi K Ganesh64
Albert Hofman20
Suman Kundu20
Francesco US Mattace-Raso203
Fernando Rivadeneira34
Eric JG Sijbrands203
Andre G Uitterlinden34
Shih-Jen Hwang96510
Ramachandran S Vasan966
Thomas J Wang967
Sven Bergmann6869
Peter Vollenweider70
Gérard Waeber70
Jaana Laitinen71
Anneli Pouta72
Paavo Zitting73
Wendy L McArdle74
Heyo K Kroemer75
Uwe Völker76
Henry Völzke77
Nicole L Glazer78
Kent D Taylor55
Tamara B Harris79
Helene Alavere27
Toomas Haller27
Aime Keis27
Mari-Liis Tammesoo27
Yurii Aulchenko20
Inês Barroso8081
Kay-Tee Khaw82
Pilar Galan838485
Serge Hercberg838485
Mark Lathrop31
Susana Eyheramendy86
Elin Org29
Siim Sõber29
Xiaowen Lu32
Ilja M Nolte32
Brenda W Penninx878889
Tanguy Corre34
Corrado Masciullo34
Cinzia Sala34
Leif Groop90
Benjamin F Voight91
Olle Melander92
Christopher J O’Donnell93
Veikko Salomaa94
Adamo Pio d’Adamo37
Antonella Fabretto95
Flavio Faletra95
Sheila Ulivi37
M Fabiola Del Greco38
Maurizio Facheris38
Francis S Collins96
Richard N Bergman97
John P Beilby9899100
Joseph Hung101100
A William Musk100102103
Massimo Mangino41
So-Youn Shin8041
Nicole Soranzo8041
Hugh Watkins4243
Anuj Goel4243
Anders Hamsten104
Pierre Gider44
Marisa Loitfelder105
Marion Zeginigg44
Dena Hernandez106
Samer S Najjar107108
Pau Navarro49
Sarah H Wild46
Anna Maria Corsi109
Andrew Singleton106
Eco JC de Geus110
Gonneke Willemsen110
Alex N Parker111
Lynda M Rose50
Brendan Buckley112
David Stott113
Marco Orru114
Manuela Uda114
LifeLines Cohort Study
Melanie M van der Klauw115
Weihua Zhang554
Xinzhong Li5
James Scott116
Yii-Der Ida Chen55
Gregory L Burke117
Mika Kähönen118
Jorma Viikari119
Angela Döring120121
Thomas Meitinger122123
Gail Davies59
John M Starr58124
Valur Emilsson15
Andrew Plump125
Jan H Lindeman126
Peter AC ’t Hoen127128
Inke R König129
EchoGen consortium
Janine F Felix204130
Robert Clarke131
Jemma C Hopewell131
Halit Ongen42
Monique Breteler20
Stéphanie Debette132
Anita L DeStefano133
Myriam Fornage134
AortaGen Consortium
Gary F Mitchell135
CHARGE Consortium Heart Failure Working Group
Nicholas L Smith136137138
KidneyGen consortium
Hilma Holm139
Kari Stefansson139140
Gudmar Thorleifsson139
Unnur Thorsteinsdottir139140
CKDGen consortium
Cardiogenics consortium
CardioGram
Nilesh J Samani62141
Michael Preuss142129
Igor Rudan46143
Caroline Hayward49
Ian J Deary5859
H-Erich Wichmann120144
Olli T Raitakari145
Walter Palmas146
Jaspal S Kooner11654
Ronald P Stolk147
J Wouter Jukema52148149
Alan F Wright49
Dorret I Boomsma110
Stefania Bandinelli150
Ulf B Gyllensten47
James F Wilson46
Luigi Ferrucci45
Reinhold Schmidt105
Martin Farrall4243
Tim D Spector41
Lyle J Palmer40100151152
Jaakko Tuomilehto153154155
Arne Pfeufer38156157
Paolo Gasparini9537
David Siscovick15813626
David Altshuler15916091161
Ruth JF Loos30
Daniela Toniolo34162
Harold Snieder32
Christian Gieger57
Pierre Meneton163
Nicholas J Wareham30
Ben A Oostra164
Andres Metspalu272829
Lenore Launer165
Rainer Rettig166
David P Strachan23
Jacques S Beckmann68167
Jacqueline CM Witteman204
Jeanette Erdmann142
Ko Willems van Dijk14168
Eric Boerwinkle169
Michael Boehnke39
Paul M Ridker501705172
Marjo-Riitta Jarvelin171172173
Aravinda Chakravarti17
Goncalo R Abecasis39
Vilmundur Gudnason1516
Christopher Newton-Cheh3591
Daniel Levy96510
Patricia B Munroe8180
Bruce M Psaty26136174138180
Mark J Caulfield8180
Dabeeru C Rao67175176180
Martin D Tobin12180
Paul Elliott1775180
Cornelia M van Duijn201784180
1Department of Health Sciences, University of Leicester, Leicester, UK
2Department of Genetics, University of Leicester, Leicester, UK
3Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
4Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA)
5Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
6Division of Biostatistics, Washington University in St. Louis, School of Medicine, Saint Louis, Missouri, USA
7Department of Genetics, Washington University in St. Louis, School of Medicine, Saint Louis, Missouri, USA
8Clinical Pharmacology and The Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
9Framingham Heart Study, Framingham, Massachusetts, USA
10National Heart, Lung and Blood Institute, Bethesda, Maryland, USA
11Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois, 1005 Lausanne, Switzerland
12University of Lausanne, Lausanne, Switzerland
13Department of Biostatistics, University of Washington, Seattle, Washington, USA
14Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
15Icelandic Heart Association, Kopavogur, Iceland
16University of Iceland, Reykajvik, Iceland
17Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
18Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland
19Cardiology, Department of Medicine, Geneva University Hospital, Geneva, Switzerland
20Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
21Department of Mathematics, Boston University, Boston, Massachusetts, USA
22Genetics Division R&D, GlaxoSmithKline, King of Prussia, Pennsylvania, USA
23Division of Community Health Sciences, St George’s, University of London, London, UK
24Pediatric Epidemiology Center, University of South Florida, Tampa, Florida, USA
25Department of Internal Medicine B, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
26Cardiovascular Health Research Unit, Division of Internal Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA
27Estonian Genome Center, University of Tartu, Tartu, Estonia
28Estonian Biocenter, Tartu, Estonia
29Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
30MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK
31Centre National de Génotypage, Commissariat à L’Energie Atomique, Institut de Génomique, Evry, France
32Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
33Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
34Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy
35Center for Human Genetic Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA
36Cardiovascular Epidemiology and Genetics, Institut Municipal d’Investigacio Medica, Barcelona Biomedical Research Park, Barcelona, Spain
37Medical Genetics IRCCS Burlo Garofolo/Università degli Studi di Trieste, Trieste, Italy
38Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy. Affiliated Institute of the University of Lübeck, Lübeck, Germany
39Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA
40Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, Crawley, Western Australia, Australia
41Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK
42Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
43Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK
44Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria
45Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA
46Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK
47Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
48NCA institute, Department of Biological Psychology, VU University, Amsterdam, The Netherlands
49MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK
50Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
51Harvard Medical School, Boston, Massachusetts, USA
52Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
53Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
54Ealing Hospital NHS Trust, Middlesex, UK
55Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
56Department of Clinical Chemistry, University of Tampere and Tampere University Hospital, Tampere, Finland
57Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
58Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK
59Department of Psychology, The University of Edinburgh, Edinburgh, UK
60Department of Public Health, Medical School, University of Split, Split, Croatia
61Department of Pharmacology, Medical School, University of Split, Split, Croatia
62Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK
63Division of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, University of Texas at Houston Health Science Center, Houston, Texas, USA
64Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA
65Center for Population Studies, National Heart Lung, and Blood Institute, Bethesda, Maryland, USA
66Division of Epidemiology and Prevention, Boston University School of Medicine, Boston, Massachusetts, USA
67Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts, USA
68Département de Génétique Médicale, Université de Lausanne, Lausanne, Switzerland
69Swiss Institute of Bioinformatics, Lausanne, Switzerland
70Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
71Finnish Institute of Occupational Health, Oulu, Finland
72National Institute for Health and Welfare, Oulu, Finland
73Department of Physiatrics, Lapland Central Hospital, Rovaniemi, Finland
74ALSPAC Laboratory, Department of Social Medicine, University of Bristol, Bristol, UK
75Institute of Pharmacology, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
76Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
77Institute for Community Medicine, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
78Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
79National Institute of Aging’s Laboratory for Epidemiology, Demography and Biometry, Bethesda, Maryland, USA
80Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
81University of Cambridge Metabolic Research Labs, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
82Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK
83U557 Institut National de la Santé et de la Recherche Médicale, Paris, France
84U1125 Institut National de la Recherche Agronomique, Paris, France
85Université Paris 13, Bobigny, France
86Department of Statistics, Pontificia Universidad Catolica de Chile, Santiago, Chile
87Department of Psychiatry/EMGO Institute/Neuroscience Campus, VU University Medical Centre, Amsterdam, The Netherlands
88Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands
89Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
90Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, Lund University, University Hospital Malmö, Malmö, Sweden
91Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
92Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, University Hospital, Malmö, Lund University, Malmö 20502, Sweden
93National Heart, Lung and Blood Institute and its Framingham Heart Study, 73 Mount Wayte Ave., Suite
94Department of Chronic Disease Prevention, THL-National Institute for Health and Welfare, Helsinki, Finland
95IRCSS Burlo Garofolo Medical Genetics, Trieste, Italy
96National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
97Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
98Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia
99Molecular Genetics, PathWest Laboratory Medicine, Nedlands, Western Australia, Australia
100Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
101School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia
102School of Medicine and Pharmcology, University of Western Australia, Crawley, Western Australia, Australia
103Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
104Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
105Department of Neurology Section of Special Neurology, Medical University Graz, Graz, Austria
106National Institute of Aging’s Laboratory of Neurogenetics, Bethesda, Maryland, USA
107Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, Maryland, USA
108Cardiovascular Research Institute, MedStar Health Research Institute, Washington Hospital Center, Washington DC, USA
109Tuscany Regional Health Agency, Florence, Italy
110EMGO+ institute, Department of Biological Psychology, VU University, Amsterdam, The Netherlands
111Amgen, Cambridge, Massachusetts, USA
112Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
113Institute of Cardiovascular and Medical Sciences, School of Medicine, University of Glasgow, UK
114Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Monserrato, Italy
115Department of Endocrinology, University Medical Center Groningen, University of Groningen, The Netherlands
116National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK
117Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
118Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland
119Department of Medicine, University of Turku and Turku University Hospital, Turku, Finland
120Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
121Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
122Institute of Human Genetics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany
123Institute of Human Genetics, Technische Universität München, Munich, Germany
124Geriatric Medicine Unit, The University of Edinburgh, Royal Victoria, Edinburgh, UK
125Cardiovascular Disease Franchise, Merck Research Laboratory, Rahway, New Jersey, USA
126Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands
127Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
128Leiden Genome Technology Center, Leiden University Medical Center, Leiden, The Netherlands
129Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany
130German Cancer Research Center, Division of Clinical Epidemiology and Aging Research, Heidelberg, Germany
131Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, UK
132Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA
133Boston University School of Public Health, Boston, Massachusetts, USA
134Brown Foundation Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA
135Cardiovascular Engineering, Inc., Norwood, Massachusetts, USA
136Department of Epidemiology, University of Washington, Seattle, Washington, USA
137Seattle Epidemiologic Research and Information, Center of the Department of Veterans Affairs Office of Research and Development, Seattle, Washington, USA
138Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA
139deCODE genetics Inc, Reykjavik, Iceland
140Faculty of Medicine, University of Iceland, Reykjavik, Iceland
141Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK
142Medizinische Klinik II, Universität zu Lübeck, Lübeck, Germany
143Croatian Centre for Global Health, University of Split Medical School, Split, Croatia
144Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität and Klinikum Grosshadern, Munich, Germany
145Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and the Department of Clinical Physiology, Turku University Hospital, Turku, Finland
146Columbia University, New York, New York, USA
147Department of Epidemiology, University Medical Center Groningen, University of Groningen, The Netherlands
148Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands
149Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands
150Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy
151Ontario Institute for Cancer Research, Toronto, Canada
152Samuel Lunenfeld Research Institute, Toronto, Canada
153National Institute for Health and Welfare, Diabetes Prevention Unit, Helsinki, Finland
154Hjelt Institute, Department of Public Health, University of Helsinki, 00014 Helsinki, Finland
155South Ostrobothnia Central Hospital, Seinajoki, Finland
156Institute of Human Genetics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
157Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
158Department of Medicine, University of Washington, Seattle, Washington, USA
159Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
160Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
161Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
162Institute of Molecuar Genetics_CNR, Pavia, Italy
163U872 Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Paris, France
164Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
165National Institute of Aging’s Laboratory for Epidemiology, Demography and Biometry, Bethesda, Marylands, USA
166Institute of Physiology, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
167Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
168Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
169Human Genetics Center, Houston, Texas, USA
170Division of Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
171Department of Biostatistics and Epidemiology, School of Public Health, Imperial College London, Norfolk Place, London, UK
172Institute of Health Sciences, University of Oulu, University of Oulu, Finland
173Biocenter, University of Oulu, Oulu, Finland
174Department of Health Services, University of Washington, Seattle, Washington, USA
175Department of Psychiatry, Washington University in St. Louis, School of Medicine, Saint Louis, Missouri, USA
176Department of Mathematics, Washington University in St. Louis, School of Medicine, Saint Louis, Missouri, USA
177MRC-HPA Centre for Environment and Health, Imperial College London, London, UK
178Centre of Medical Systems Biology, Erasmus University Medical Center, Rotterdam, The Netherlands
179A list of consortium members is supplied in the Supplementary Note.
180These authors contributed equally.

High blood pressure is a major risk factor for coronary heart disease and stroke4. Large genome-wide association studies in Europeans have reported 29 novel loci for systolic and diastolic blood pressure (SBP and DBP) where alleles have effect sizes of up to 0.5-1mm Hg1-3. Even small increments in blood pressure levels have important effects on cardiovascular morbidity and mortality at the population level5. We undertook a genome-wide association study of two further blood pressure phenotypes, pulse pressure (PP, the difference between SBP and DBP), a measure of stiffness of the main arteries, and mean arterial pressure (MAP), a weighted average of SBP and DBP. Both PP and MAP are predictive of hypertension6 and cardiovascular disease7-9.

This study was undertaken by the International Consortium of Blood Pressure Genome-Wide Association Studies (ICBP-GWAS) which aims to further the understanding of the genetic architecture underlying blood pressure. The initial publication by this consortium1 studied SBP and DBP with discovery GWAS among 69,395 people and a combined sample of ~200,000 Europeans. The two blood pressure phenotypes reported here, namely PP and MAP, were not previously analysed. All but one study that was included in the discovery GWAS of the study of SBP and DBP were included in the discovery GWAS stage of this study. In addition, a further 6 studies not included in the previous study1 were included here bringing our discovery GWAS sample size to 74,064.

We first conducted a genome-wide association meta-analysis of PP and MAP in 74,064 individuals of European ancestry from 35 studies (Supplementary Table 1A). Genotypes were imputed using HapMap. To account for effects of anti-hypertensive treatments, we imputed underlying SBP and DBP by adding a constant to each2,3. Associations were adjusted for age, age2, sex and body mass index. We combined results across studies using an inverse variance weighted meta-analysis and, to correct for residual test statistic inflation, applied genomic control (GC) both to study-level association statistics and to the meta-analysis (λGC=1.08 for PP, λGC=1.12 for MAP)10. The QQ plots show an excess of extreme values largely accounted for by a modest number of genomic regions (Supplementary Figures 1 (a) – (b)). Independent follow-up analyses were performed in 48,607 individuals of European ancestry (Online Methods and Supplementary Note).

SNPs in 12 regions showed genome-wide significant association (P<5×10-8) with either PP or MAP in our discovery data (Stage 1) (Supplementary Figures 1 (c) – (d)), including two novel regions for PP (7q22.3 near PIK3CG, P=1.2×10-10 and 11q24.3 near ADAMTS8, P=8.5×10-11; Table 1) and 10 regions previously associated with SBP and DBP (Supplementary Table 2A for PP, Supplementary Table 2B for MAP)1-3. For follow-up in a series of independent cohorts we selected 99 SNPs comprising those with P<1×10-5 for either PP or MAP and SNPs reported in recent large genome-wide association studies of SBP and DBP1-3 to evaluate their effects on PP and MAP (Stage 2: Online Methods, Supplementary Note).

After meta-analysis of the Stage 1 and Stage 2 data (Supplementary Table 2C), the two novel regions showing genome-wide association with PP after Stage 1 (near PIK3CG and near ADAMTS8) remained genome-wide significant. In addition, we found genome-wide significant associations for SNPs at two further novel loci for PP (at 4q12 near CHIC2/PDGFRA and 8q24.12 in NOV), two novel loci for MAP (3p21.31 in MAP4, 10q25.3 near ADRB1), and one locus for both traits (2q24.3 near FIGN) (Table 1 and Figure 1) which has not previously shown an association with SBP or DBP in Europeans but which has recently been associated with SBP in east Asians (see Supplementary Note)11. Forest plots of the Stage 1 effect sizes and standard errors are shown in Supplementary Figure 2. The novel signals for MAP were strongly associated with both SBP and DBP (P=7.7×10-7 to P=1.8×10-12), reflecting the high inter-correlations among these three blood pressure traits12,13. For the sentinel SNPs in three of the novel PP loci, the estimated effects on SBP were in the opposite direction to the effects on DBP (Table 1, Figure 2, Supplementary Tables 2D and 2E). Our findings show that analyses of PP and MAP reveal loci influencing blood pressure phenotypes which may not be detectable by studying SBP and DBP separately. Identification of novel genetic associations could help inform understanding about possible distinct mechanisms underlying relationships of PP with vascular risk14,15.

Five additional loci for PP and 19 loci for MAP reaching genome-wide significance (P<5×10-8, Stage 1 and Stage 2 combined) were recently shown to be associated with SBP/DBP1-3 (Supplementary Tables 2A and 2B). We used sentinel SNPs from both the novel and known regions showing genome-wide significant associations with PP or MAP in the combined Stage 1 and 2 data to create weighted risk scores for: i) PP (10 independent SNPs) and; ii) MAP (22 SNPs) (Supplementary Table 2F). We studied the associations of both risk scores with hypertension and blood pressure related outcomes including coronary heart disease, heart failure, stroke, echocardiographic measures of left ventricular structure, pulse wave velocity, renal function and renal failure. Adjusting for multiple testing for the 12 traits evaluated (P=0.05/12=4.1×10-3), the PP SNP risk score was associated with prevalent hypertension (P=7.9×10-6), incident stroke (P=4.9×10-4) and coronary heart disease (P=4.3×10-4), and the MAP SNP risk score was associated with hypertension (P=5.1×10-16), coronary heart disease (P=4.0 ×10-20), stroke (P=0.0019) and left ventricular wall thickness (P=2.1×10-4) (Supplementary Table 3A), confirming the clinical relevance of these measures of blood pressure phenotype8,9. For a range of blood pressure related outcomes (see Supplementary Note), we compared P values for the PP risk score and a series of 1000 permutations of SBP risk scores, each based on 10 of the 26 blood pressure SNPs associated with SBP but not PP, constraining the selection of SNPs to have similar sized effects for SBP as those of the 10 PP SNPs. The PP risk score had a significantly (P<0.05) greater association with risk of ischemic stroke than the SBP risk score (Supplementary Note and Supplementary Table 3B).

None of the genes in the identified novel regions is a strong candidate for blood pressure regulation, although several are implicated in mechanisms that may influence blood pressure. The most significant association with PP is within a putative mRNA clone (AF086203) spanning ~13.7kb at 7q22.3, 94kb upstream of PIK3CG (rs17477177, P=2.3×10-13, Table 1 and Figure 1a). PIK3CG encodes the phosphoinositide-3-kinase, catalytic, gamma polypeptide protein which phosphorylates phosphoinositides and modulates extracellular signals. This region was earlier associated with mean platelet volume, platelet count, and platelet aggregation16-18, but the sentinel SNPs reported in those studies are independent of SNP rs17477177 reported here (r2<0.01). Mice lacking the catalytic subunit of PI3Kγ have shown resistance to SBP-lowering effects of beta-adrenergic receptor agonists19; PI3Kγ activity is increased in the failing human heart and associated with down-regulation of beta-adrenergic receptors in the plasma membrane20. The second locus for PP located at 11q24.3 spans 35.5kb with the top-ranking SNP (rs11222084, P=1.9×10-11, Figure 1b) lying 1.6kb downstream of ADAMTS-8. This gene is highly expressed in macrophage-rich areas of human atherosclerotic plaques and may affect extracellular matrix remodeling21. The third locus for PP spans 28.5kb at 8q24.12 with the sentinel SNP (rs2071518, P=3.7×10-9, Figure 1c) located in the 3’UTR of NOV which encodes the nephroblastoma overexpressed (CCN3) protein, associated with angiogenesis, proliferation, and inhibition of vascular smooth muscle cell growth and migration22, and with reduced neointimal thickening in mice null for CCN323. Mice with mutations in NOV that truncate the NOV protein exhibit abnormal cardiac development24. Of the genes evaluated for expression in human aortic samples at the novel PP loci, NOV showed by far the highest expression levels (Supplementary Note and Supplementary Figure 3). The fourth locus for PP is 4q12 with the top-ranking SNP (rs871606, P=1.3×10-8, Figure 1d) located 76.7kb downstream of CHIC2 which encodes a cysteine-rich hydrophobic domain containing protein associated with acute myeloid leukaemia25. This SNP is located 296kb upstream of PDGFRA which encodes platelet-derived growth factor receptor alpha, a cell surface receptor for members of the platelet-derived growth factor family involved in kidney development. Variants in PDGFRA have been associated with red blood cell count and other haematological indices26 but are independent (r2<0.3) of rs871606.

For MAP we identified two novel loci. The first locus for MAP is at 10q25.3, 22.3kb upstream of ADRB1 (rs2782980, P=2.5×10-9, Figure 1e). ADRB1 encodes the beta-1-adrenergic receptor, which mediates the effects of the stimulatory G protein and cAMP/protein kinase A pathway to increase heart rate and myocardial contraction. Polymorphisms in this gene have been associated with resting heart rate, response to beta-blockers27, and hypertension28. ADRB1 knockout mice have no difference in heart rate or blood pressure compared with the wild type but do exhibit a significant reduction in the response of both phenotypes to catecholamines29. SNP rs2782980 is associated with expression of an ADRB1 transcript in brain tissue (Supplementary Note and Supplementary Figure 4A). The second locus for MAP spans over 300kb at 3p21.31 with the top-ranking SNP (rs319690, P=2.7×10-8, Figure 1f) lying within an intron of the microtubule associated protein 4 gene, MAP4. Coating of microtubules by MAP4 may inhibit beta adrenergic receptor recycling and number, as seen in cardiac hypertrophy and failure30. MAP4 was detectably expressed in human aortic samples (Supplementary Note and Supplementary Figure 3).

The locus associated both with PP (SNP rs13002573, P=1.8×10-8, Figure 1g) and MAP (rs1446468, P= 6.5×10-12, Figure 1h) is in an intergenic region spanning ~280kb at 2q24.3. Although the two signals are ~50kb apart and statistically independent (r2=0.075), rs13002573 is highly correlated (r2=1 in HapMap CEU population, r2=0.87 in HapMap JPT+CHB) with rs16849225 which has recently been reported as showing association with SBP in a GWAS of 19,608 subjects of east Asian origin with follow-up in a further 30,765 individuals (combined result: P=3.5×10-11) 11 (see Supplementary Note). In our combined dataset in 116,998 Europeans, the association P value for rs13002573 with SBP was P=3.25×10-7. The top PP SNP lies ~320kb upstream of FIGN and ~430kb downstream of GRB14 (growth factor receptor-bound protein 14). Relatively little is known regarding FIGN (fidgetin).

We report six novel loci associated with PP and MAP based on genome-wide discovery and follow-up in over ~120,000 individuals, and a further locus (near FIGN) not previously reported in Europeans. Our results expand knowledge of the genetic architecture of blood pressure and PP regulation and may give clues as to possible novel targets for blood pressure therapies.


Online Methods

Pulse pressure was defined as systolic minus diastolic pressure and MAP as 2/3 diastolic plus 1/3 systolic pressure. A two-staged analysis was used to discover genes associated with PP and MAP.

Stage 1 samples and analyses

Stage 1 was a meta-analysis of directly genotyped and imputed SNPs from population-based or control samples from case-control studies, in the International Consortium of Blood Pressure Genome-wide Association Studies (ICBP-GWAS). The characteristics of the 35 studies, including demographics, genotyping arrays, quality control filters and statistical analysis methods used are listed in Supplementary Tables 1A and 1B. Imputation of allele dosage of ungenotyped SNPs in HapMap CEU v21a or v22 was carried out by each of the studies using MACH31, IMPUTE32 or BIMBAM33 with parameters and pre-imputation filters as specified in Supplementary Table 1B. SNPs were excluded from analysis if the study-specific imputation quality (r2.hat in MACH or .info in IMPUTE) was <0.3. In total, up to 2652054 genotyped or imputed autosomal SNPs were analyzed. Full details of the models, methods, and corrections for antihypertensive treatment are provided in the Supplementary methods. All analyses assumed an additive genetic model and were adjusted for sex, age, age2, body mass index and ancestry principal components. In related individuals, regression methods that account for relatedness were applied. All study-specific effect estimates and coded alleles were oriented to the forward strand of the HapMap release 22 with the alphabetically higher allele as the coded allele. To capture loss of power due to imperfect imputation, we estimated “N effective” as the sum of the study-specific products of the imputation quality metric and the sample size. No filtering on minor allele frequency was done. Genomic control was carried out on study-level data and inverse variance weighting was used for meta-analysis of Stage 1. The meta-analysis results were subject to genomic control. Lambda estimates are given in Supplementary Table 1A.

Selection of SNPs for Stage 2

We aimed in Stage 2 to follow up SNPs which had evidence of association with PP or MAP and, for completeness, to evaluate the effects on PP and MAP of SNPs reported in recent large genome-wide association studies of SBP and DBP1-3. All SNPs with P<1×10-5 for association with either PP or MAP (or both) were divided into independent regions based on LD and the most significant SNP was selected from each region. Within the FIGN region, different SNPs were associated with PP and with MAP and both SNPs were followed up in Stage 2. For SNPs with an N effective <75% of total N, a proxy was also included if it had P <1×10-5 and an r2>0.6 with the top SNP (this occurred for one SNP). For all regions that had previously shown association with SBP or DBP1-3, the sentinel SNP for PP and MAP and the previously reported SNP for SBP and DBP were followed up. In all, 99 SNPs were followed up in Stage 2 (Supplementary Note), comprising: 44 SNPs from 22 loci with PP or MAP associations (P<1×10-5) in Stage 1 data and with previously reported SBP or DBP associations; 47 SNPs from 45 loci with PP or MAP associations (P<1×10-5) in Stage 1 data only and; 8 SNPs from 7 loci with previously reported SBP or DBP associations and no association (P<1×10-5) with PP or MAP in the Stage 1 data.

Stage 2

The characteristics of the Stage 2 studies, including the genotyping and imputation approaches, are described in Supplementary Tables 1A and 1B and the details of corrections for treatment described in the Supplementary Note. For the 99 SNPs selected for follow-up, the Stage 2 studies followed the analysis approach adopted in the Stage 1 analyses. Meta-analysis was done using the inverse variance weights method.

Pooled analysis of first and second stage samples

Meta-analysis from stages 1 and 2 was conducted using inverse variance weighting and genomic control applied. A threshold of 5×10-8 was taken for genome-wide significance.

Calculation of risk scores

We calculated risk scores based on the most significantly associated SNP from all regions which were genome-wide significant after meta-analysis of Stages 1 and 2 for i) PP (10 SNPs) and ii) MAP (22 SNPs) (Supplementary Table 2F). Each risk score was constructed using an approach described in the Supplementary Note and was tested for association with hypertension, coronary artery disease, stroke, hypertension, chronic kidney disease, heart failure, microalbuminuria, and with continuous traits left ventricular mass, left ventricular wall thickness, pulse wave velocity, serum creatinine, eGFR and urinary albumin:creatinine ratio (Supplementary Table 3).

Additional analyses

Identification of potentially functional SNPs in LD with the reported sentinel SNPs, eQTL analyses and expression analyses in human aortic samples were also carried out as discussed in the Supplementary Note and Supplementary Figures 3 and 4.


Supplementary Material 1

Notes

FN4Competing Financial Interests

A.C. is managed by Johns Hopkins Medicine. I.B. and spouse own stock in Incyte Ltd and GlaxoSmithKline. A.N.P is an employee of Amgen. G.F.M. is owner of Cardiovascular Engineering, Inc, a company that designs and manufactures devices that measure vascular stiffness. The company uses these devices in clinical studies that evaluate the effects of diseases and interventions on vascular stiffness. V.M. is an employee of GlaxoSmithKline plc. A.Plump is an employee of Merck and Co, Inc.

A number of the participating studies and authors are members of the CHARGE and Global BPgen consortia. Many funding mechanisms by NIH/NHLBI, European, and private funding agencies contributed to this work and a full list is provided in the Supplementary Note.

Contributions

ICBP-GWAS PP/MAP Working and Writing Sub-Group (alphabetical order) M.J.C., P.E. (co-chair), T.J., P.B.M., P.F.O’R., M.D.T. (co-chair), C.M.V. (co-chair), G.C.V., L.V.W. ICBP-GWAS Steering Committee (alphabetical order) G.R.A., M.Bochud, M.Boehnke, MJ.C. (co-chair), A.C., G.B.E., P.E., T.B.H., M-R.J, A.D.J., T.J., M.G.L., L.L., D.L. (co-chair), P.B.M.(co-chair), C.N-C. (co-chair), B.M.P., K.M.R., A.V.S., M.D.T., C.M.V, G.C. V. Analysis L.V.W., G.C.V., P.F.O’R., T.J. Expression analyses V.E., P.H., A.D.J., D.L., J.H.L., C.P.N, A.Plump, P.A.C ’t H., K.W.V. Cohort contributions (alphabetical order): Study concept/design: AGES: T.A., V.G., T.B.H., L.L., A.V.S., AortaGen Consortium: G.F.M., ARIC: E.B., A.C., S.K.G., ASPS: H.Schmidt, R.S., BLSA: L.F., B58C-T1DGC: D.P.S., B58C-WTCCC: D.P.S., BHS: L.J.P., CardioGram Consortium: N.J.S., C4D Consortium: R.Clarke, R.Collins, CHS: J.C.B., N.L.G., B.M.P., K.M.R., K.D.T., CHARGE Consortium Heart Failure Working Group: N.L.S., CoLaus: V.M., P.Vollenweider, G.Waeber, CROATIA-Korcula: C.H., CROATIA-Split: M.Boban, I.R., CROATIA-Vis: A.F.W., DeCode Genetics: H.H., K.S., G.T., U.T., DGI controls: D.A., L.G., C.N-C., ENGAGE: J.E., I.R.K., EGCUT: H.A., A.M., EPIC: K-T.K., ERF: B.A.O., Fenland: N.J.W., FUSION: M.Boehnke, F.S.C., R.N.B., J.T., INGI CARL: A.P.d’A., P.Gasparini, INGI-FVG: A.P.d’A., P.Gasparini, INCHIANTI: S.Bandinelli., Y.M., KORA S3: C.G., M.Laan, E.O., KORA F4: T.M, H-E.W., LifeLines: R.P.S., M.M.V., LOLIPOP: J.C.C., P.E., J.S.K., LBC1921/LBC1936: I.J.D., J.M.S., MICROS: A.Pfeufer, MESA: X.G., W.P., MIGen controls: O.M., C.J.O., V.S., D.Siscovick, NESDA: B.W.P., H.Snieder, NEURO-CHARGE Consortium: M.Breteler M.Fornage, NFBC1966: M-R.J, P.Z, NSPHS: U.B.G., S.E.H., NTR: D.I.B., E. J.C. deG., ORCADES: H.C., J.F.W., PROCARDIS controls: M.Farrall, A.Hamsten, J.F.P., H.W., PROSPER/PHASE: B.B., J.W.J., D.Stott, RSI/RSII/RSIII: A.Hofman, C. M.V., J.C.M.W., SardiNIA: G.A., M.U., SHIP: M.D., H.K.K., R.R., U.V., H.V., SUVIMAX: P.Gilan, S.Hercberg, P.M., TwinsUK: T.D.S., WGHS: P.M.R., YFS: M.K., T.L., O.T.R., J.V. Phenotype data acquisition/QC: AGES: T.A., V.G., T.B.H., L.L., ARIC: A.C., S.K.G., A.C.M, D.C.R., ASPS: M.Loitfelder, R.S., BLSA: S.N., B58C-T1DGC: D.P.S., B58C-WTCCC: D.P.S., BHS: J.P.B., J.H., C4D Consortium: R.Clarke, R.Collins, J.C.H., CHS: B.M.P., CoLaus: M.Bochud, V.M., P.Vollenweider, CROATIA-Korcula: C.H., O.P., CROATIA-Split: M.Boban, I.R., DGI controls: L.G., C.N-C., EGCUT: H.A., A.K., A.M., M-L.T., EPIC: N.J.W., Fenland: N.J.W., FHS: S.-J.H., M.G.L., D.L., R.S.V., T.J.W., FUSION: J.T., INGI CARL: A.F., F.F., P.Gasparini, S.U., INGI FVG: A.F., F.F., P.Gasparini, S.U., INGI-Val Borbera: C.Masciullo, C.S., D.T., INCHIANTI: A.M.C., KORA S3: C.G., KORA F4: A.D., LifeLines: M.M.V., LOLIPOP: J.C.C., J.S.K., J.S., LBC1921/LBC1936: I.J.D., L.M.L., J.M.S., MICROS: M.Facheris, A.Pfeufer, MESA: X.G., W.P., MIGen controls: G.L., O.M., C.J.O., V.S., D.Siscovick, NESDA: : X.Lu, I.M.N., B.W.P., H.Snieder, NEURO-CHARGE Consortium: M.Breteler, S.D., A.L.D., M.Fornage, NFBC1966: P.E., M-R.J., J.Laitinen, A.Pouta, P.Z., NSPHS: J.A.C., U.B.G., S.E.H., P.J.T., NTR: D.I.B., E.J.C.deG., G.Willemsen, ORCADES: S.H.W., J.F.W., PROCARDIS controls: J.F.P., PROSPER/PHASE: D.Stott, S.T., RSI/RSII/RSIII: F.U.S.M.R., E.J.G.S., C.M.V., G.C.V., J.C.M.W., SardiNIA: M.O., M.U., SHIP: M.D., R.R., H.V., SUVIMAX: P.Gilan, M.Lathrop, TwinsUK: T.D.S., WGHS: D.I.C., A.N.P., YFS: M.K., T.L., O.T.R., J.V. Genotype data acquisition/QC: AGES: A.V.S., ARIC: A.C., G.B.E., S.K.G., A.C.M., D.C.R, G.S., ASPS: P.Gider, H. Schmidt, M.Z., BLSA: D.Hernandez, B58C-T1DGC: S.Heath, W.L.McA., B58C-WTCCC: W.L.McA., BHS: J.P.B., R.J.W., C4D Consortium: J.C.H., H.O., CHS: J.C.B., N.L.G., K.D.T., CoLaus: V.M., P.Vollenweider, CROATIA-Korcula: C.H., O.P., CROATIA-Split: I.R., CROATIA-Vis: V.V., DGI controls: D.A., B.F.V., EGCUT: T.E., T.H., EPIC: N.J.W., Fenland: R.J.F.L., J.Luan, N.J.W., FHS: S.-J.H., M.G.L., FUSION: F.S.C., INGI CARL: A.P.d’A., INGI FVG: A.P.d’A., INGI Val Borbera: C.Masciullo, C.S., D.T., INCHIANTI: A.S., KORA S3: C.G., M.Laan, E.O., KORA F4: T.M, H-E.W., LifeLines: B.Z.A., LOLIPOP: J.C.C., J.S.K., J.S., W.Z., LBC1921/LBC1936: G.D., I.J.D., MICROS: I.P., MESA: X.G., MIGen controls: G.L., O.M., C.J.O., V.S., D.S., NESDA: J.F., X.Lu, I.M.N., B.W.P., H.Snieder, NFBC1966: P.E., M-R.J., J.Laitinen, P.Z., NSPHS: J.P., P.J.T., NTR: D.I.B., E.J.C.deG., J-J.H., G.Willemsen, ORCADES: H.C., J.F.W., PROCARDIS controls: A.G., J.F.P., PROSPER/PHASE: S.T., RSI/RSII/RSIII: F.R., A.G.U., SardiNIA: G.A., SHIP: H.K.K., U.V., H.V., SUVIMAX: S.Heath, M.Lathrop, TwinsUK: M.M., S-Y.S, N.S., F.Z., WGHS: P.M.R., YFS: T.L., O.T.R. Data analysis: AGES: T.A., A.V.S, ARIC: A.C., G.B.E., A.C.M., V.P., D.C.R, G.S., ASPS: P.Gider, H. Schmidt, M.Z., BLSA: T.T. B58C-T1DGC: D.P.S., B58C-WTCCC: D.Hadley, D.P.S., BHS: W.A.M., L.J.P., R.J.W., C4D Consortium: J.C.H., H.O., CHS: J.C.B., N.L.G., K.M.R., CoLaus: S.Bergmann, M.Bochud, T.J., CROATIA-Korcula: C.H., O.P., CROATIA-Split: C.H., CROATIA-Vis: V.V., DGI controls: P.A., C.N-C., B.F.V., EchoGen Consortium: J.F.F., EGCUT: T.E., T.H., ENGAGE: M.P., EPIC: I.B., R.J.F.L., N.J.W., J.H.Z., ERF: A.C.J.W.J., Y.A., Fenland: R.J.F.L, J.Luan., FHS: S.-J.H., M.G.L., FUSION: A.U.J., INGI CARL: N.P., INGI FVG: N.P., INGI Val Borbera: T.C., G.P., C.S., D.T., KORA S3: S.E., S.S., KORA F4: B.K., LifeLines: B.Z.A., LOLIPOP: J.C.C., J.S.K., X.Li, J.S., W.Z., LBC1921/LBC1936: L.M.L., MICROS: F.D-G.M., MESA: X.G., W.P., MIGen controls: G.L., NESDA: J.F., X.Lu., NEURO-CHARGE Consortium: S.D., A.L.D, M.Fornage, NFBC1966: P.F.O’R., NSPHS: J.A.C., W.I., NTR: J-J.H., ORCADES: P.N., S.H.W., J.F.W., PROCARDIS controls: M.Farrall, A.G., J.F.P., PROSPER/PHASE: J.W.J., S.T., RSI/RSII/RSIII: N.A., S.K., C.M.V., G.C.V., SardiNIA: J.L.B-G., SHIP: U.V., SUVIMAX: T.J., P.M., TwinsUK: N.S., F.Z., WGHS: D.I.C., L.M.R., YFS: T.L., O.T.R.


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