title: Blood pressure loci identified with a gene-centric array.
abstract: Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
authors.affiliation: Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK. t.johnson@qmul.ac.uk
authors.forename: Toby
authors.initials: T
authors.lastname: Johnson
authors.forename: Tom R
authors.initials: TR
authors.lastname: Gaunt
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Newhouse
authors.forename: Sandosh
authors.initials: S
authors.lastname: Padmanabhan
authors.forename: Maciej
authors.initials: M
authors.lastname: Tomaszewski
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.forename: Richard W
authors.initials: RW
authors.lastname: Morris
authors.forename: Ioanna
authors.initials: I
authors.lastname: Tzoulaki
authors.forename: Eoin T
authors.initials: ET
authors.lastname: O'Brien
authors.forename: Neil R
authors.initials: NR
authors.lastname: Poulter
authors.forename: Peter
authors.initials: P
authors.lastname: Sever
authors.forename: Denis C
authors.initials: DC
authors.lastname: Shields
authors.forename: Simon
authors.initials: S
authors.lastname: Thom
authors.forename: Sasiwarang G
authors.initials: SG
authors.lastname: Wannamethee
authors.forename: Peter H
authors.initials: PH
authors.lastname: Whincup
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Brown
authors.forename: John M
authors.initials: JM
authors.lastname: Connell
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Dobson
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Howard
authors.forename: Charles A
authors.initials: CA
authors.lastname: Mein
authors.forename: Abiodun
authors.initials: A
authors.lastname: Onipinla
authors.forename: Sue
authors.initials: S
authors.lastname: Shaw-Hawkins
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.forename: Ian N M
authors.initials: IN
authors.lastname: Day
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.forename: Alison H
authors.initials: AH
authors.lastname: Goodall
authors.forename: F Gerald
authors.initials: FG
authors.lastname: Fowkes
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.forename: Paul
authors.initials: P
authors.lastname: Elliott
authors.forename: Vesela
authors.initials: V
authors.lastname: Gateva
authors.forename: Peter S
authors.initials: PS
authors.lastname: Braund
authors.forename: Paul R
authors.initials: PR
authors.lastname: Burton
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nelson
authors.forename: Martin D
authors.initials: MD
authors.lastname: Tobin
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.forename: Nicola
authors.initials: N
authors.lastname: Glorioso
authors.forename: Hani
authors.initials: H
authors.lastname: Neuvrith
authors.forename: Erika
authors.initials: E
authors.lastname: Salvi
authors.forename: Jan A
authors.initials: JA
authors.lastname: Staessen
authors.forename: Andrea
authors.initials: A
authors.lastname: Stucchi
authors.forename: Nabila
authors.initials: N
authors.lastname: Devos
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Plouin
authors.forename: Jean
authors.initials: J
authors.lastname: Tichet
authors.forename: Peeter
authors.initials: P
authors.lastname: Juhanson
authors.forename: Elin
authors.initials: E
authors.lastname: Org
authors.forename: Margus
authors.initials: M
authors.lastname: Putku
authors.forename: Siim
authors.initials: S
authors.lastname: Sõber
authors.forename: Gudrun
authors.initials: G
authors.lastname: Veldre
authors.forename: Margus
authors.initials: M
authors.lastname: Viigimaa
authors.forename: Anna
authors.initials: A
authors.lastname: Levinsson
authors.forename: Annika
authors.initials: A
authors.lastname: Rosengren
authors.forename: Dag S
authors.initials: DS
authors.lastname: Thelle
authors.forename: Claire E
authors.initials: CE
authors.lastname: Hastie
authors.forename: Thomas
authors.initials: T
authors.lastname: Hedner
authors.forename: Wai K
authors.initials: WK
authors.lastname: Lee
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.forename: Björn
authors.initials: B
authors.lastname: Wahlstrand
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hardy
authors.forename: Andrew
authors.initials: A
authors.lastname: Wong
authors.forename: Jackie A
authors.initials: JA
authors.lastname: Cooper
authors.forename: Jutta
authors.initials: J
authors.lastname: Palmen
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.forename: George A
authors.initials: GA
authors.lastname: Wells
authors.forename: Harm-Jan
authors.initials: HJ
authors.lastname: Westra
authors.forename: Marcel G M
authors.initials: MG
authors.lastname: Wolfs
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Franzosi
authors.forename: Anuj
authors.initials: A
authors.lastname: Goel
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: John F
authors.initials: JF
authors.lastname: Peden
authors.forename: Udo
authors.initials: U
authors.lastname: Seedorf
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sambrook
authors.forename: Jonathan
authors.initials: J
authors.lastname: Stephens
authors.forename: Juan-Pablo
authors.initials: JP
authors.lastname: Casas
authors.forename: Fotios
authors.initials: F
authors.lastname: Drenos
authors.forename: Michael V
authors.initials: MV
authors.lastname: Holmes
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimaki
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.forename: Tina
authors.initials: T
authors.lastname: Shah
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.forename: John
authors.initials: J
authors.lastname: Whittaker
authors.forename: Chris
authors.initials: C
authors.lastname: Wallace
authors.forename: Christian
authors.initials: C
authors.lastname: Delles
authors.forename: Maris
authors.initials: M
authors.lastname: Laan
authors.forename: Diana
authors.initials: D
authors.lastname: Kuh
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.forename: Fredrik
authors.initials: F
authors.lastname: Nyberg
authors.forename: Daniele
authors.initials: D
authors.lastname: Cusi
authors.forename: Robert
authors.initials: R
authors.lastname: Roberts
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.forename: Alice V
authors.initials: AV
authors.lastname: Stanton
authors.forename: Anna F
authors.initials: AF
authors.lastname: Dominiczak
authors.forename: Martin
authors.initials: M
authors.lastname: Farrall
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Caulfield
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Munroe
mesh_terms: D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: C506952:ATP2B1 protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D053499:Plasma Membrane Calcium-Transporting ATPases; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C
references.citation: Nat Genet. 1992 Apr;1(1):72-5
references.pmid: 1338766
references.citation: Am J Hum Genet. 2004 Apr;74(4):765-9
references.pmid: 14997420
references.citation: Genome Biol. 2008;9(9):R137
references.pmid: 18798982
references.citation: Nat Genet. 2010 Jul;42(7):579-89
references.pmid: 20581827
references.citation: J Physiol. 2008 Jan 15;586(2):353-66
references.pmid: 18006579
references.citation: Science. 2007 Jun 8;316(5830):1497-502
references.pmid: 17540862
references.citation: Nature. 2011 Sep 11;478(7367):103-9
references.pmid: 21909115
references.citation: Nat Methods. 2008 Sep;5(9):829-34
references.pmid: 19160518
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D871-5
references.pmid: 21037257
references.citation: Circulation. 2010 Jun 1;121(21):2302-9
references.pmid: 20479155
references.citation: J Am Soc Nephrol. 2001 Mar;12(3):606-615
references.pmid: 11181811
references.citation: Nat Genet. 2010 Jul;42(7):570-5
references.pmid: 20562874
references.citation: Am J Hum Genet. 2003 Jul;73(1):212-4
references.pmid: 12865991
references.citation: Nat Genet. 1994 Aug;7(4):551
references.pmid: 7951330
references.citation: Curr Opin Cell Biol. 2002 Dec;14(6):692-9
references.pmid: 12473341
references.citation: Nat Genet. 1996 Aug;13(4):399-408
references.pmid: 8696333
references.citation: Am J Hum Genet. 2006 Mar;78(3):498-504
references.pmid: 16465623
references.citation: Am J Hum Genet. 2011 Jan 7;88(1):6-18
references.pmid: 21194676
references.citation: Nat Genet. 2008 May;40(5):592-599
references.pmid: 18391953
references.citation: Nature. 2010 Oct 28;467(7319):1061-73
references.pmid: 20981092
references.citation: Nature. 2007 Jun 14;447(7146):799-816
references.pmid: 17571346
references.citation: PLoS One. 2008;3(10):e3583
references.pmid: 18974833
references.citation: Nat Genet. 2011 Sep 11;43(10):1005-11
references.pmid: 21909110
references.citation: Nat Genet. 2011 Mar;43(3):246-52
references.pmid: 21297633
references.citation: J Biol Chem. 2010 Jul 9;285(28):21689-97
references.pmid: 20466723
references.citation: Comp Funct Genomics. 2003;4(6):609-25
references.pmid: 18629027
references.citation: PLoS Genet. 2010 Oct 28;6(10):e1001177
references.pmid: 21082022
references.citation: J Hypertens. 2011 Jan;29(1):62-9
references.pmid: 21045733
references.citation: PLoS Genet. 2010 Jun 10;6(6):e1000977
references.pmid: 20548944
references.citation: Hypertension. 2010 Dec;56(6):1069-76
references.pmid: 21060006
references.citation: Heredity (Edinb). 2005 Sep;95(3):221-7
references.pmid: 16077740
references.citation: PLoS Genet. 2007 May 18;3(5):e74
references.pmid: 17511519
references.citation: Nat Genet. 2009 Mar;41(3):348-53
references.pmid: 19219041
references.citation: Nat Genet. 2009 Jun;41(6):677-87
references.pmid: 19430479
references.citation: Circulation. 2009 Jan 20;119(2):243-50
references.pmid: 19118251
references.citation: Nat Biotechnol. 2009 Jan;27(1):66-75
references.pmid: 19122651
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7403-8
references.pmid: 10377427
references.citation: Eur J Hum Genet. 2007 Dec;15(12):1239-45
references.pmid: 17726486
references.citation: Nat Genet. 2006 Feb;38(2):209-13
references.pmid: 16415888
references.citation: Arch Biochem Biophys. 2008 Aug 1;476(1):65-74
references.pmid: 18328800
references.citation: Crit Rev Biochem Mol Biol. 2008 Jan-Feb;43(1):3-36
references.pmid: 18307107
references.citation: Nat Genet. 2009 May;41(5):527-34
references.pmid: 19396169
references.citation: N Engl J Med. 1994 Jun 9;330(23):1629-33
references.pmid: 8177268
references.citation: Hum Mol Genet. 2011 Jun 1;20(11):2285-95
references.pmid: 21422096
references.citation: J Exp Med. 2005 Feb 7;201(3):409-18
references.pmid: 15684321
references.citation: Int J Biochem Cell Biol. 2010 Mar;42(3):429-32
references.pmid: 19647094
references.citation: Nature. 1980 Nov 27;288(5789):373-6
references.pmid: 6253831
references.citation: Genet Epidemiol. 2010 Jul;34(5):522-7
references.pmid: 20552655
references.citation: J Hypertens. 1999 Feb;17(2):151-83
references.pmid: 10067786
references.citation: Nat Genet. 2011 Jun;43(6):531-8
references.pmid: 21572416
references.citation: Nat Rev Genet. 2008 May;9(5):356-69
references.pmid: 18398418
references.citation: J Cell Biol. 1992 Sep;118(6):1443-53
references.pmid: 1522116
references.citation: Hypertension. 2011 May;57(5):903-10
references.pmid: 21444836
references.citation: Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10526-30
references.pmid: 7937987
references.citation: Nature. 2010 Aug 5;466(7307):714-9
references.pmid: 20686566
references.citation: Nat Genet. 2009 Jun;41(6):666-76
references.pmid: 19430483
references.citation: Stat Med. 2005 Oct 15;24(19):2911-35
references.pmid: 16152135
references.citation: J Hypertens. 2010 Jan;28(1):65-75
references.pmid: 19770777
references.citation: PLoS Genet. 2010 Aug 05;6(8):
references.pmid: 20700443
references.citation: Nat Genet. 2010 Jun;42(6):504-7
references.pmid: 20453838
references.citation: Nature. 1995 Sep 21;377(6546):239-42
references.pmid: 7545787