Sixteen novel genetic loci influence blood pressure and cardiovascular risk

Georg B. Ehret, Patricia B. Munroe, Andrew D. Johnson, Murielle Bochud, Kenneth M. Rice, Michael Boehnke, Bruce M. Psaty, Albert V. Smith, Paul Elliott,

Cornelia M. van Duijn, Gonçalo R Abecasis, Aravinda Chakravarti, Christopher Newton-Cheh, Daniel Levy, Mark J. Caulfield, Toby Johnson

On behalf of 351 co-authors from 234 institutions and 24 Countries worldwide

Nature: Advanced On Line 11th September 2011

Barts and The London Cardiovascular Biomedical Research Unit

William Harvey Research Institute

Hypertension & Blood Pressure• 1 billion hypertensives worldwide• BP causes 50% cardiovascular death• Up to 4.5% global disease burden• Complex trait - multiple risk factors

– 30-50% of BP genes– 50-70% lifestyle factors e.g. salt, weight, alcohol

Success in Mendelian Disorders of BPGenetic architecture – new biology & potential targets

WHO guidelines. Levy D. Nature Genetics 2009, Newton-Cheh C. Nature Genetics 2009

Genomewide Association Studies • Range of chip technologies for population scans• Impute up to 2.5m SNPs from HAPMAP• Genomewide significance 5 x10-8

• Adjusted for age, age2, BMI, treatment adjusted by +15/10 mm Hg

• QC- call rate, HWE, genomic control before and after meta-analysis

• Inverse variance weighted meta-analysis• Staged wet bench genotyping in replication

International Consortium for blood pressure Genome-wide studies (ICBP GWAS)

Discovery Meta-analysis of Genome Scans from 69,935 Europeans

Validation of top SBP and DBP hits- 133,661k Europeans

Meta-analysis of European data – 203K people

Non-European follow-up of signals – 75k people

South Asians (22k), East Asians (31k), African ancestry (17K)

Identifies 16 novel genes for SBP or DBP

Extension of some findings to other ancestries

Risk of hypertension, CHD, Stroke, LV structure, Renal Damage

Demographics for EuropeansStudy N %

women

Age (SD) in years

BP in mmHg (SD)

SBP DBPStage 0 GWASAGES Reykjavik 3,219 58 51.0 (6.0) 132.0 (17.0) 83.0 (10.0)Amish 1,598 50.3 51.6 (16.6) 121.7 (16.3) 74.2 (9.4)ARIC 8,052 53 54.0 (6.0) 118.0 (17.0) 71.0 (10.0)

B58C–T1DGC 2,580 51 44.3 (0.3) 126.7 (14.6) 79.0 (10.0)

B58C–WTCCC 1,473 50 44.9 (0.4) 126.7 (15.2) 79.1 (10.2)

BLSA 708 44 42.4 (13.2) 119.5 (15.0) 77.3 (10.2)CHS 3,277 61 72.0 (5.0) 135.0 (21.0) 70.0 (11.0)CoLaus 4,969 53 51.7 (9.5) 127.3 (17.4) 79.4 (10.8)

EPIC- Norfolk 2,100 54 57.2 (7.8) 136.7 (19.1) 83.9 (11.9)

ERF (EUROSPAN) 1,240 60.1 48.3 (14.7) 139.3 (20.7) 79.9 (10.0)Fenland 1,401 56 45.0 (7.3) 122.8 (16.3) 75.5 (10.7)FHS 8,096 54 38.0 (9.0) 119.0 (15.0) 77.0 (10.0)InCHIANTI 562 55 56.9 (14.5) 138.4 (20.1) 81.4 (10.1)KORA 1,644 51 52.5 (10.1) 133.4 (18.5) 81.8 (10.9)MICROS (EUROSPAN) 1,096 56.6 45.3 (16.1) 132.9 (20.2) 79.9 (11.1)NFBC1966 4,761 52 31.2 (0.4) 125.2 (13.8) 77.5 (11.7)NSPHS (EUROSPAN) 644 53.3 47.0 (20.7) 122.8 (18.7) 74.1 (7.9)ORCADES (EUROSPAN) 700 53.4 53.6 (15.7) 130.2 (19.3) 76.3 (10.1)RS-I 4,737 60 68.0 (8.0) 139.0 (22.0) 74.0 (11.0)

RS-II 1,760 56 64.0 (7.0) 143.0 (21.0) 79.0 (11.0)

SardiNIA 3,998 57 40.8 (15.3) 128.7 (28.4) 79.7 (17.3)SHIP 3,306 53 45.0 (13.9) 133.1 (20.2) 83.5 (11.3)SU.VI.MAX 1,673 60 50.5 (6.2) 120.9 (12.3) 78.0 (8.1)

TwinsUK 873 100 45.8 (11.9) 122.9 (15.4) 78.2 (10.3)VIS (EUROSPAN) 697 58.4 56.8 (15.6) 137.6 (24.5) 80.5 (11.5)Controls from case-control studiesDGI 1,277 51 56.1 (8.7) 133.3 (18.4) 80.1 (10.0)FUSION 1,038 49 58.2 (10.7) 139.4 (19.3) 81.5 (10.3)MIGen 1,121 38 48.9 (8.3) 127.1 (17.8) 80.2 (11.6)

PROCARDIS 795 37 58.9 (6.9) 134.7 (18.6) 82.8 (10.0)

SBP beta & P val DBP beta & P Val HTN beta & P val

Association results of 29 variants of SBP, DBP, and HTN

unpublished &confidential

Known role of genes at lociGene locus Putative function ns SNP eQTL

Mov10 Helicase ?telomerase near a Rho Kinase Yes Yes

Mecom MDS1 myelodysplasia/ EV11 No Yes

SLC4A7 Na HCo3 exchanger Yes Yes

SLC39A8 Cadmium transport/ BMI/HDL Yes Yes

GUCY1A3-1B Guanylate cyclase subunits No No

NPR3 Natriuretic peptide receptor No No

EBF1 Near ADAM 19 (renal disease) No No

HFE Hemochromatosis variant Yes No

BAT2-5 HLA region lung cancer/ RA No No

CACNB2 3’ Neuronal calcium channel No No

PLCE1 Podocytes/ familial glomerulosclerosis No No

FLJ 32810 –TMEM13

FLJ –(Rho type GTPASE) TMEM progesterone receptor No No

ADM Adrenomedullin No No

FES-Furin FES (oncogene) FURIN activates ENAC, EDN No Yes

GOSR2 Golgi SNAP receptor - HTN No Yes

JAG1 Alagille syndrome - HTN No No

GNAS-EDN3 G coupled Alpha subunit/endothelin 3 Yes No

Extension to other ancestrieslocus pheno

EA.betaSE EA.P SA.betaSE SA.P AA.betaSE AA.PMOV10 DBP 0.1703 (0.1745) 0.3290 0.5834 (0.2133) 6.25E-03 -0.1658 (0.485) 0.7324FGF5 SBP 1.31 (0.1881) 3.28E-12 0.5993 (0.2267) 0.0082 0.1453 (0.4992) 0.7709FGF5 DBP 0.7491 (0.1117) 2.01E-11 0.5068 (0.1345) 1.65E-04 0.4731 (0.3523) 0.1793NPR3-C5orf23SBP 0.7596 (0.1531) 6.98E-07 0.3306 (0.1465) 0.0240 0.1842 (0.2566) 0.4729NPR3-C5orf23DBP 0.4269 (0.09439) 6.12E-06 0.2109 (0.1041) 0.0428 -0.0247 (0.1723) 0.8862CYP17A1-NT5C2SBP 1.393 (0.2501) 2.54E-08 1.09 (0.2493) 1.22E-05 0.2235 (0.7117) 0.7535CYP17A1-NT5C2DBP 0.8189 (0.157) 1.84E-07 0.7375 (0.148) 6.31E-07 0.3871 (0.4852) 0.4249PLEKHA7 SBP 0.4767 (0.1953) 0.0146 0.03355 (0.3749) 0.9287 0.6417 (0.3617) 0.0761PLEKHA7 DBP 0.2938 (0.1194) 0.0139 -0.02754 (0.2152) 0.8982 0.462 (0.2477) 0.0622FLJ32810-TMEM133SBP -0.4661 (0.1513) 2.07E-03 -0.3139 (0.1466) 0.0322 -0.2927 (0.3354) 0.3829FLJ32810-TMEM133DBP -0.3198 (0.09324) 6.04E-04 -0.2657 (0.1052) 0.0115 0.0887 (0.2264) 0.6952ATP2B1 SBP 1.421 (0.1687) 3.65E-17 1.156 (0.2762) 2.84E-05 -0.2636 (0.3788) 0.4866ATP2B1 DBP 0.7985 (0.1049) 2.75E-14 0.5777 (0.1587) 2.71E-04 -0.1091 (0.2646) 0.6802CYP1A1-ULK3SBP 1.118 (0.192) 5.75E-09 0.2525 (0.2379) 0.2885 0.4129 (0.4768) 0.3865CYP1A1-ULK3DBP 0.6106 (0.1171) 1.86E-07 0.1151 (0.1411) 0.4147 -0.0452 (0.3306) 0.8913FES SBP 1.398 (0.3453) 5.16E-05 0.3445 (0.1736) 0.0472 0.5318 (0.2801) 0.0576FES DBP 0.775 (0.2128) 2.70E-04 0.2532 (0.1296) 0.0508 0.4136 (0.19) 0.0295JAG1 SBP 0.5748 (0.1505) 1.34E-04 0.2965 (0.1399) 0.0341 0.3707 (0.2143) 0.0837JAG1 DBP 0.3485 (0.0929) 1.76E-04 0.2766 (0.1) 5.71E-03 0.1476 (0.1438) 0.3046GNAS-EDN3DBP NA NA 0.6087 (0.2031) 2.72E-03 0.3031 (0.2056) 0.1404

ICBP conclusions• Meta-analysis and validation confirms 29 SNPs at 28 loci associated

with BP• 16 are novel loci - one locus PLCD3 not confirmed• 18/28 loci have no clear mechanism for BP influence• 8/28 loci associated with amino acid change• 6 with expression QTLs (some with multiple transcripts)• Some extension to other ancestries• Pathway analysis and testing up to 130 metabolic traits negative• SNP x BMI and a SNP x sex no associations

• Pulse Pressure and MAP has identified 6 loci• Louise Wain, Martin Tobin and Paul Elliott • Nature Genetics 11th/9/11 and poster BHS 14th/9/11

ICBP Steering Committee

Gonçalo R Abecasis, Murielle Bochud, Michael Boehnke, Mark J. Caulfield (co-chair), Aravinda Chakravarti, Cornelia M. van Duijn, Georg B. Ehret, Paul Elliott, Tamara B. Harris, Marjo Riitta Järvelin, Andrew D. Johnson, Toby Johnson, Martin G. Larson,

Lenore Launer, Daniel Levy (co-chair), Patricia B. Munroe (co-chair), Christopher Newton-Cheh (co-chair), Bruce M. Psaty, Kenneth M.

Rice, Albert V. Smith, Martin D. Tobin, Germaine C. Verwoert

Toby JohnsonMark CaulfieldDan LevyChris Newton-ChehCornelia van DuijnPaul Elliott

Georg Ehret

Gonçalo Abecasis

Bruce Psaty

Aravinda Chakravarti

Patricia Munroe Ken Rice Murielle Bochud Andrew Johnson Dan Chasman Albert Smith

Georg B. Ehret1,2,3*, Patricia B. Munroe4*, Kenneth M. Rice5*, Murielle Bochud2,6*, Andrew D. Johnson7,8*, Daniel I. Chasman9,10*, Albert V. Smith11,12*, Martin D. Tobin13, Germaine C. Verwoert14,15,16, Shih-Jen Hwang7,17,8, Vasyl Pihur1, Peter Vollenweider18, Paul F. O'Reilly19, Abbas Dehghan14,15,16, Jennifer L Bragg-Gresham20, Alexander Teumer21, Nicole L. Glazer22, Lenore Launer23, Jing Hua Zhao24, Yurii Aulchenko14, Simon Heath25, Siim Sõber26, Afshin Parsa27, Jian'an Luan24, Pankaj Arora2, Najaf Amin14, Feng Zhang29, Gavin Lucas30, Andrew A. Hicks31, Anne U. Jackson32, John F Bakker33, Toshiko Tanaka34, Sarah H. Wild35, Igor Rudan36,37, Wilmar Igl38, Yuri Milaneschi34, Alex N. Parker39, Cristiano Fava40, John C. Chambers19,41, Ervin R. Fox42, Meena Kumari43, Min Jin Go44, Pim van der Harst45, Wen Hong Linda Kao46, Marketa Sjögren40, Vinay D. G47, Myriam Alexander48, Yasuharu Tabara49, Sue S. Hawkins4, Peter H. Whincup50, Yongmei Liu51, Gang Shi52, Johanna Kuusisto53, Bamidele Tayo54, Mark Seielstad55,56, Xueling Sim57, Khanh-Dung Hoang Nguyen1, Ying Wu58, Tom R. Gaunt59, N. Charlotte Onland-Moret60,61, Matthew N. Cooper62, Carl G.P. Platou63, Elin Org26, Rebecca Hardy64, Santosh Dahgam65, Jutta Palmen66, Veronique Vitart67, Peter S. Braund68,69, Tatiana Kuznetsova70, Cuno S.P.M. Uiterwaal60, Adebowale Adeyemo71, Walter Palmas72, Harry Campbell36, Barbara Ludwig73, Maciej Tomaszewski68,69, Ioanna Tzoulaki74,75, Nicholette P. Allred76, CARDIoGRAM consortium77, CKDGen Consortium77, KidneyGen Consortium77, EchoGen consortium77, Heart and Vascular Health Study78, Thor Aspelund11,12, Melissa Garcia23, Yen-Pei C. Chang27, Jeffrey R. O'Connell27, Nanette I. Steinle27, Diederick E. Grobbee60, Dan E. Arking1, Sharon L. Kardia79, Alanna C. Morrison80, Dena Hernandez81, Samer Najjar82,83, Wendy L. McArdle84, David Hadley50, Morris J. Brown85, John M. Connell86, Aroon D. Hingorani87, Ian N.M. Day59, Debbie A. Lawlor59, John P. Beilby88,89,

ICBP GWAS Nature co-authors

Robert W. Lawrence62, Robert Clarke90, Jemma C Hopewell90, Halit Ongen33, Albert W. Dreisbach42, Yali Li91, J H. Young92, Joshua C. Bis22, Mika Kähönen93, Terho Lehtimöki94, Olli Raitakari95, Jorma Viikari96, Linda S. Adair97, Nanette R. Lee98, Ming-Huei Chen99, Matthias Olden100,101, Cristian Pattaro31, Judith A. Hoffman Bolton102, Anna Köttgen103,102, Sven Bergmann104,105, Vincent Mooser106, Nish Chaturvedi107, Timothy M. Frayling108, Muhammad Islam109, Tazeen H. Jafar109, Jeanette Erdmann110, Smita R. Kulkarni111, Stefan R. Bornstein73, Jürgen Grässler73, Leif Groop112,113, Benjamin F. Voight114, Philip Howard115, Andrew Taylor43, Simonetta Guarrera116, Giuseppe Matullo117,116, Fulvio Ricceri117,116, Paolo Vineis118,116, Valur Emilsson119, Andrew Plump119, Inês Barroso120,121, Kay-Tee Khaw48, Alan B. Weder122, Steven C. Hunt123, Yan V. Sun79, Francis S. Collins124, Bergman N. Richard125, Lori L. Bonnycastle124, Laura J. Scott32, Heather M. Stringham32, Leena Peltonen120,126,127,128, Markus Perola126, Erkki Vartiainen126, Stefan-Martin Brand129,130, Jan A. Staessen70, Thomas J. Wang7,131, Paul R. Burton13,69, Maria Soler Artigas13, Kurt K. Lohman132, Megan E. Rudock51, Susan R Heckbert133,134, Nicholas L Smith133,135,134, Kerri L Wiggins136, Ayo Doumatey71, Daniel Shriner71, Gudrun Veldre26,137, Margus Viigimaa138,139, Sanjay Kinra140, Dorairajan Prabhakaran141, Vikal Tripathy141, Carl D. Langefeld76, Annika Rosengren142, Dag S. Thelle143, Anna Maria Corsi144, Andrew Singleton81, Gina Hilton1, Colin A. McKenzie145, Tunde Salako146, Naoharu Iwai147, Yoshikuni Kita148, Toshio Ogihara149, Takayoshi Ohkubo150, Tomonori Okamura147, Hirotsugu Ueshima151, Satoshi Umemura152, Susana Eyheramendy153, Thomas Meitinger154,155, H.-Erich Wichmann156,157,158, Yoon Shin Cho44, Hyung-Lae Kim44, Jong-Young Lee44, James Scott159, Joban S. Sehmi159,41, Weihua Zhang19, Bo Hedblad40, Peter Nilsson40, George D. Smith160, Andrew Wong64, Narisu Narisu124, Alena Stančáková53, Leslie J. Raffel161, Jie Yao161, Sekar Kathiresan162,28, Chris O'Donnell163,28,10, Steven M. Schwartz133, M. Arfan Ikram14,16, Will T. Longstreth Jr.164, Thomas H. Mosley165, Sudha Seshadri166, Nick R.G. Shrine13, Louise V. Wain13, Mario A. Morken124, Amy J. Swift124, Jaana Laitinen167, Inga Prokopenko168,169, Paavo Zitting170, Jackie A. Cooper66, Steve E. Humphries66, John Danesh48, Asif Rasheed171, Anuj Goel33, Anders Hamsten172, Hugh Watkins33, Stephan J.L. Bakker173, Wiek H. van Gilst45, Radha K. Mani47, Charles J. Spurgeon47,

Chittaranjan S. Yajnik111, Albert Hofman14, Francesco U.S. Mattace Raso14,15, Ben A. Oostra174, Fernando Rivadeneira14,15, Edward G Lakatta175, Marco Orru176,177, Angelo Scuteri175, Rick Twee-Hee Ong56,57,178, Marcus Dörr179, Heyo K. Kroemer180, Uwe Völker21, Henry Völzke181, Pilar Galan182, Serge Hercberg182, Mark Lathrop25, Diana Zelenika25, Panos Deloukas120, Massimo Mangino29, Tim D. Spector29, Guangju Zhai29, James F. Meschia183, Michael A. Nalls184, Pankaj Sharma185, Janos Terzic186, Kranthi Kumar M. J47, Matthew Denniff68, Ewa Zukowska-Szczechowska187, Lynne E. Wagenknecht76, F. Gerald R. Fowkes188, Fadi J. Charchar189, Peter E.H. Schwarz190, Caroline Hayward67, Xiuqing Guo161, Charles Rotimi71, Michiel L. Bots60, Eva Brand191, Nilesh J. Samani68,69, Ozren Polasek192, Philippa J. Talmud66, Fredrik Nyberg65,193, Diana Kuh64, Maris Laan26, Kristian Hveem63, Lyle J. Palmer62,194, Yvonne T. van der Schouw60, Juan P. Casas195, Karen L. Mohlke58, Santhi K. Ganesh196, Tien Y. Wong197,198, E Shyong Tai199,57,200, Richard S. Cooper54, Markku Laakso53, Dabeeru C. Rao201, Tamara B. Harris23, Richard W. Morris202, Anna F. Dominiczak203, Mika Kivimaki87, Michael G. Marmot87, Tetsuro Miki49, Danish Saleheen171,48, Giriraj R. Chandak47, Josef Coresh204, Gerjan Navis205, Veikko Salomaa126, Bok-Ghee Han44, Xiaofeng Zhu91, Jaspal S. Kooner159,41, Olle Melander40, Paul M Ridker9,206,10, Stefania Bandinelli207, Ulf B. Gyllensten38, Alan F. Wright67, James F. Wilson35, Luigi Ferrucci34, Martin Farrall33, Jaakko Tuomilehto208,209,210,211, Peter P. Pramstaller31,212, Roberto Elosua30,213, Nicole Soranzo120,29, Eric J.G. Sijbrands14,15, David Altshuler214,114, Ruth J.F. Loos24, Alan R. Shuldiner27,215, Christian Gieger156, Pierre Meneton216, Andre G. Uitterlinden14,15,16, Nicholas J. Wareham24, Vilmundur Gudnason11,12, Jerome I. Rotter161,217, Rainer Rettig218, Manuela Uda176, David P. Strachan50, Jacqueline C.M. Witteman14,16, Anna-Liisa Hartikainen219, Jacques S. Beckmann104,104, Eric Boerwinkle220, Ramachandran S. Vasan7,221, Michael Boehnke32, Martin G. Larson7,222, Marjo-Riitta Järvelin19,223,224,225, Bruce M. Psaty226,134*, Gonçalo R Abecasis20*, Aravinda Chakravarti1*, Paul Elliott19,227*, Cornelia M. van Duijn14,228*, Christopher Newton-Cheh28,114*, Daniel Levy7,17,8*##, Mark J. Caulfield4*##, Toby Johnson4*

Thanks• The Study Participants• British Genetics of Hypertension Study• ASCOT Investigators• Wellcome Trust Case Control Consortium• ICBP GWAS, Global BP Gen• Funders - Wellcome Trust, MRC, BHF, NIHR• Multiple European, US and Indian, Asian

funders