Transcript Slide 1

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
William Harvey Research Institute
Barts and The London Cardiovascular
Biomedical Research Unit
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 BP
Genetic 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
Study
N
%
wom
en
Age (SD) in BP in mmHg (SD)
years
Demographics for Europeans
SBP
Stage 0 GWAS
AGES Reykjavik
Amish
ARIC
3,219
1,598
8,052
58
50.3
53
B58C–T1DGC
2,580
B58C–WTCCC
DBP
51.0 (6.0)
51.6 (16.6)
54.0 (6.0)
132.0 (17.0)
121.7 (16.3)
118.0 (17.0)
83.0 (10.0)
74.2 (9.4)
71.0 (10.0)
51
44.3
(0.3)
126.7 (14.6)
79.0 (10.0)
1,473
50
44.9
(0.4)
126.7 (15.2)
79.1 (10.2)
BLSA
CHS
CoLaus
708
3,277
4,969
44
61
53
42.4 (13.2)
72.0 (5.0)
51.7 (9.5)
119.5 (15.0)
135.0 (21.0)
127.3 (17.4)
77.3 (10.2)
70.0 (11.0)
79.4 (10.8)
EPIC- Norfolk
2,100
54
57.2
136.7 (19.1)
83.9 (11.9)
ERF (EUROSPAN)
Fenland
FHS
InCHIANTI
KORA
MICROS (EUROSPAN)
NFBC1966
NSPHS (EUROSPAN)
ORCADES (EUROSPAN)
RS-I
1,240
1,401
8,096
562
1,644
1,096
4,761
644
700
4,737
60.1
56
54
55
51
56.6
52
53.3
53.4
60
48.3 (14.7)
45.0 (7.3)
38.0 (9.0)
56.9 (14.5)
52.5 (10.1)
45.3 (16.1)
31.2 (0.4)
47.0 (20.7)
53.6 (15.7)
68.0 (8.0)
139.3
122.8
119.0
138.4
133.4
132.9
125.2
122.8
130.2
139.0
(20.7)
(16.3)
(15.0)
(20.1)
(18.5)
(20.2)
(13.8)
(18.7)
(19.3)
(22.0)
79.9 (10.0)
75.5 (10.7)
77.0 (10.0)
81.4 (10.1)
81.8 (10.9)
79.9 (11.1)
77.5 (11.7)
74.1 (7.9)
76.3 (10.1)
74.0 (11.0)
RS-II
1,760
56
64.0
(7.0)
143.0 (21.0)
79.0 (11.0)
SardiNIA
SHIP
SU.VI.MAX
3,998
3,306
1,673
57
53
60
40.8 (15.3)
45.0 (13.9)
50.5 (6.2)
128.7 (28.4)
133.1 (20.2)
120.9 (12.3)
79.7 (17.3)
83.5 (11.3)
78.0 (8.1)
TwinsUK
873
100
VIS (EUROSPAN)
697 58.4
Controls from case-control studies
DGI
1,277
51
FUSION
1,038
49
MIGen
1,121
38
45.8 (11.9)
56.8 (15.6)
122.9 (15.4)
137.6 (24.5)
78.2 (10.3)
80.5 (11.5)
56.1 (8.7)
58.2 (10.7)
48.9 (8.3)
133.3 (18.4)
139.4 (19.3)
127.1 (17.8)
80.1 (10.0)
81.5 (10.3)
80.2 (11.6)
PROCARDIS
58.9
134.7 (18.6)
82.8 (10.0)
795
37
(7.8)
(6.9)
SBP beta & P val
DBP beta & P Val
HTN beta & P val
Association results of 29 variants of SBP, DBP, and HTN
unpublished &
confidential
Gene locus
Putative function
Mov10
Helicase ?telomerase near a Rho Kinase
ns SNP
eQTL
Yes
Mecom
Yes
Known
role
of
genes
at
loci
MDS1 myelodysplasia/ EV11
No
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
Yes
Extension to other ancestries
locus
pheno
EA.betaSE
MOV10
DBP
0.1703 (0.1745)
FGF5
SBP
1.31 (0.1881)
FGF5
DBP
0.7491 (0.1117)
NPR3-C5orf23
SBP
0.7596 (0.1531)
NPR3-C5orf23
DBP
0.4269 (0.09439)
CYP17A1-NT5C2
SBP
1.393 (0.2501)
CYP17A1-NT5C2
DBP
0.8189 (0.157)
PLEKHA7 SBP
0.4767 (0.1953)
PLEKHA7 DBP
0.2938 (0.1194)
FLJ32810-TMEM133
SBP
-0.4661 (0.1513)
FLJ32810-TMEM133
DBP
-0.3198 (0.09324)
ATP2B1
SBP
1.421 (0.1687)
ATP2B1
DBP
0.7985 (0.1049)
CYP1A1-ULK3
SBP
1.118 (0.192)
CYP1A1-ULK3
DBP
0.6106 (0.1171)
FES
SBP
1.398 (0.3453)
FES
DBP
0.775 (0.2128)
JAG1
SBP
0.5748 (0.1505)
JAG1
DBP
0.3485 (0.0929)
GNAS-EDN3DBP
NA
EA.P
0.3290
3.28E-12
2.01E-11
6.98E-07
6.12E-06
2.54E-08
1.84E-07
0.0146
0.0139
2.07E-03
6.04E-04
3.65E-17
2.75E-14
5.75E-09
1.86E-07
5.16E-05
2.70E-04
1.34E-04
1.76E-04
NA
SA.betaSE
0.5834 (0.2133)
0.5993 (0.2267)
0.5068 (0.1345)
0.3306 (0.1465)
0.2109 (0.1041)
1.09 (0.2493)
0.7375 (0.148)
0.03355 (0.3749)
-0.02754 (0.2152)
-0.3139 (0.1466)
-0.2657 (0.1052)
1.156 (0.2762)
0.5777 (0.1587)
0.2525 (0.2379)
0.1151 (0.1411)
0.3445 (0.1736)
0.2532 (0.1296)
0.2965 (0.1399)
0.2766 (0.1)
0.6087 (0.2031)
SA.P
6.25E-03
0.0082
1.65E-04
0.0240
0.0428
1.22E-05
6.31E-07
0.9287
0.8982
0.0322
0.0115
2.84E-05
2.71E-04
0.2885
0.4147
0.0472
0.0508
0.0341
5.71E-03
2.72E-03
AA.betaSE
-0.1658 (0.485)
0.1453 (0.4992)
0.4731 (0.3523)
0.1842 (0.2566)
-0.0247 (0.1723)
0.2235 (0.7117)
0.3871 (0.4852)
0.6417 (0.3617)
0.462 (0.2477)
-0.2927 (0.3354)
0.0887 (0.2264)
-0.2636 (0.3788)
-0.1091 (0.2646)
0.4129 (0.4768)
-0.0452 (0.3306)
0.5318 (0.2801)
0.4136 (0.19)
0.3707 (0.2143)
0.1476 (0.1438)
0.3031 (0.2056)
AA.P
0.7324
0.7709
0.1793
0.4729
0.8862
0.7535
0.4249
0.0761
0.0622
0.3829
0.6952
0.4866
0.6802
0.3865
0.8913
0.0576
0.0295
0.0837
0.3046
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
Georg Ehret
Paul Elliott
Patricia Munroe
Gonçalo Abecasis
Ken Rice
Cornelia van Duijn
Murielle Bochud
Andrew Johnson
Aravinda Chakravarti
Chris Newton-Cheh
Dan Chasman
Dan Levy
Albert Smith
Mark Caulfield
Bruce Psaty
Toby Johnson
ICBP GWAS Nature co-authors
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,
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