Blood pressure loci identified with a gene-centric array.

Tom R Gaunt; Sandosh Padmanabhan; Maciej Tomaszewski; Meena Kumari; Richard W Morris; Ioanna Tzoulaki; Eoin T O'Brien; Neil R Poulter; Peter Sever; Denis C Shields; Simon Thom; Sasiwarang G Wannamethee; Peter H Whincup; Richard J Dobson; Philip J Howard; Charles A Mein; Abiodun Onipinla; Sue Shaw-Hawkins; Yun Zhang; George Davey Smith; Ian N M Day; Debbie A Lawlor; F Gerald Fowkes; Christopher P Nelson; Nicola Glorioso; Hani Neuvrith; Erika Salvi; Jan A Staessen; Andrea Stucchi; Nabila Devos; Xavier Jeunemaitre; Pierre-François Plouin; Jean Tichet; Peeter Juhanson; Margus Putku; Siim Sõber; Gudrun Veldre; Margus Viigimaa; Anna Levinsson; Annika Rosengren; Dag S Thelle; Claire E Hastie; Thomas Hedner; Wai K Lee; Björn Wahlstrand; Rebecca Hardy; Andrew Wong; Jackie A Cooper; Jutta Palmen; Li Chen; Alexandre F R Stewart; George A Wells; Harm-Jan Westra; Marcel G M Wolfs; Maria Grazia Franzosi; Mark Lathrop; Juan-Pablo Casas; Fotios Drenos; Michael V Holmes; Mika Kivimaki; Sonia Shah; Tina Shah; Philippa J Talmud; John Whittaker; Christian Delles; Diana Kuh; Steve E Humphries; Fredrik Nyberg; Daniele Cusi; Robert Roberts; Lude Franke; Alice V Stanton; Aroon D Hingorani; Christopher Newton-Cheh; Toby Johnson; Vesela Gateva; Martin D Tobin; Murielle Bochud; Lachlan Coin; Samer S Najjar; Jing Hua; Simon C Heath; Susana Eyheramendy; Konstantinos Papadakis; Benjamin F Voight; Laura J Scott; Feng Zhang; Martin Farrall; Toshiko Tanaka; Chris Wallace; John C Chambers; Kay-Tee Khaw; Peter Nilsson; Pim van der Harst; Silvia Polidoro; Diederick E Grobbee; N Charlotte Onland-Moret; Michiel L Bots; Louise V Wain; Katherine S Elliott; Alexander Teumer; Jian'an Luan; Gavin Lucas; Johanna Kuusisto; Paul R Burton; David Hadley; Wendy L McArdle; I-chip For Psoriasis Wellcome Trust Case Control Consortium; Morris Brown; Anna Dominiczak; Stephen J Newhouse; Nilesh J Samani; John Webster; Eleftheria Zeggini; Jacques S Beckmann; Sven Bergmann; Noha Lim; Kijoung Song; Peter Vollenweider; Gerard Waeber; Dawn M Waterworth; Xin Yuan; Leif Groop; Marju Orho; Alessandra Allione; Alessandra Di Gregorio; Simonetta Guarrera; Salvatore Panico; Fulvio Ricceri; Valeria Romanazzi; Carlotta Sacerdote; Paolo Vineis; Inês Barroso; Manjinder S Sandhu; Robert N Luben; Gabriel J Crawford; Pekka Jousilahti; Markus Perola; Michael Boehnke; Lori L Bonnycastle; Francis S Collins; Anne U Jackson; Karen L Mohlke; Heather M Stringham; Timo T Valle; Cristen J Willer; Richard N Bergman; Mario A Morken; Angela Döring; Christian Gieger; Thomas Illig; Thomas Meitinger; Elin Org; Arne Pfeufer; H Erich Wichmann; Sekar Kathiresan; Jaume Marrugat; Christopher J O'Donnell; Stephen M Schwartz; David S Siscovick; Isaac Subirana; Nelson B Freimer; Anna-Liisa Hartikainen; Mark I McCarthy; Paul F OReilly; Leena Peltonen; Anneli Pouta; Paul E de Jong; Harold Snieder; Wiek H van Gilst; Robert Clarke; Anuj Goel; Anders Hamsten; John F Peden; Udo Seedorf; Christine Syv; Giovanni Tognoni; Edward G Lakatta; Serena Sanna; Paul Scheet; David Schlessinger; Angelo Scuteri; Marcus Dörr; Florian Ernst; Stephan B Felix; Georg Homuth; Roberto Lorbeer; Thorsten Reffelmann; Rainer Rettig; Uwe Völker; Pilar Galan; Ivo G Gut; Serge Hercberg; G Mark Lathrop; Diana Zeleneka; Panos Deloukas; Nicole Soranzo; Frances M Williams; Guangju Zhai; Veikko Salomaa; Markku Laakso; Roberto Elosua; Nita G Forouhi; Henry Völzke; Cuno S Uiterwaal; Yvonne T van der Schouw; Mattijs E Numans; Giuseppe Matullo; Gerjan Navis; Göran Berglund; Sheila A Bingham; Jaspal S Kooner; Andrew D Paterson; John M Connell; Stefania Bandinelli; Luigi Ferrucci; Hugh Watkins; Tim D Spector; Jaakko Tuomilehto; David Altshuler; David P Strachan; Maris Laan; Pierre Meneton; Nicholas J Wareham; Manuela Uda; Marjo-Riitta Jarvelin; Vincent Mooser; Olle Melander; Ruth J F Loos; Paul Elliott; Gonçalo R Abecasis; Mark Caulfield; Patricia B Munroe; Tony Attwood; Stephanie Belz; Peter Braund; Jessy Brocheton; François Cambien; Jason Cooper; Abi Crisp-Hihn; Patrick Diemert; Jeanette Eardman; Nicola Foad; Tiphaine Godefroy; Alison H Goodall; Jay Gracey; Emma Gray; Rhian Gwilliams; Susanne Heimer; Christian Hengstenberg; Jennifer Jolley; Unni Krishnan; Heather Lloyd-Jones; Ulrika Liljedahl; Ingrid Lugauer; Per Lundmark; Seraya Maouche; Jasbir S Moore; Gilles Montalescot; David Muir; Elizabeth Murray; Chris P Nelson; Jessica Neudert; David Niblett; Karen O'Leary; Willem H Ouwehand; Helen Pollard; Carole Proust; Angela Rankin; Augusto Rendon; Catherine M Rice; Hendrik B Sager; Jennifer Sambrook; Gerd Schmitz; Michael Scholz; Laura Schroeder; Heribert Schunkert; Jonathan Stephens; Ann-Christine Syvannen; Stefanie Tennstedt

doi:10.1016/j.ajhg.2011.10.013

Blood pressure loci identified with a gene-centric array.

Tom R Gaunt, Sandosh Padmanabhan, Maciej Tomaszewski, Meena Kumari, Richard W Morris, Ioanna Tzoulaki, Eoin T O'Brien, Neil R Poulter, Peter Sever, Denis C Shields, Simon Thom, Sasiwarang G Wannamethee, Peter H Whincup, Richard J Dobson, Philip J Howard, Charles A Mein, Abiodun Onipinla, Sue Shaw-Hawkins, Yun Zhang, George Davey SmithIan N M Day, Debbie A Lawlor, F Gerald Fowkes, Christopher P Nelson, Nicola Glorioso, Hani Neuvrith, Erika Salvi, Jan A Staessen, Andrea Stucchi, Nabila Devos, Xavier Jeunemaitre, Pierre-François Plouin, Jean Tichet, Peeter Juhanson, Margus Putku, Siim Sõber, Gudrun Veldre, Margus Viigimaa, Anna Levinsson, Annika Rosengren, Dag S Thelle, Claire E Hastie, Thomas Hedner, Wai K Lee, Björn Wahlstrand, Rebecca Hardy, Andrew Wong, Jackie A Cooper, Jutta Palmen, Li Chen, Alexandre F R Stewart, George A Wells, Harm-Jan Westra, Marcel G M Wolfs, Maria Grazia Franzosi, Mark Lathrop, Juan-Pablo Casas, Fotios Drenos, Michael V Holmes, Mika Kivimaki, Sonia Shah, Tina Shah, Philippa J Talmud, John Whittaker, Christian Delles, Diana Kuh, Steve E Humphries, Fredrik Nyberg, Daniele Cusi, Robert Roberts, Lude Franke, Alice V Stanton, Aroon D Hingorani, Christopher Newton-Cheh (Collaborator), Toby Johnson (Collaborator), Vesela Gateva (Collaborator), Martin D Tobin (Collaborator), Murielle Bochud (Collaborator), Lachlan Coin (Collaborator), Samer S Najjar (Collaborator), Jing Hua (Collaborator), Simon C Heath (Collaborator), Susana Eyheramendy (Collaborator), Konstantinos Papadakis (Collaborator), Benjamin F Voight (Collaborator), Laura J Scott (Collaborator), Feng Zhang (Collaborator), Martin Farrall (Collaborator), Toshiko Tanaka (Collaborator), Chris Wallace (Collaborator), John C Chambers (Collaborator), Kay-Tee Khaw (Collaborator), Peter Nilsson (Collaborator), Pim van der Harst (Collaborator), Silvia Polidoro (Collaborator), Diederick E Grobbee (Collaborator), N Charlotte Onland-Moret (Collaborator), Michiel L Bots (Collaborator), Louise V Wain (Collaborator), Katherine S Elliott (Collaborator), Alexander Teumer (Collaborator), Jian'an Luan (Collaborator), Gavin Lucas (Collaborator), Johanna Kuusisto (Collaborator), Paul R Burton (Collaborator), David Hadley (Collaborator), Wendy L McArdle (Collaborator), I-chip For Psoriasis Wellcome Trust Case Control Consortium (Collaborator), Morris Brown (Collaborator), Anna Dominiczak (Collaborator), Stephen J Newhouse (Collaborator), Nilesh J Samani (Collaborator), John Webster (Collaborator), Eleftheria Zeggini (Collaborator), Jacques S Beckmann (Collaborator), Sven Bergmann (Collaborator), Noha Lim (Collaborator), Kijoung Song (Collaborator), Peter Vollenweider (Collaborator), Gerard Waeber (Collaborator), Dawn M Waterworth (Collaborator), Xin Yuan (Collaborator), Leif Groop (Collaborator), Marju Orho (Collaborator), Alessandra Allione (Collaborator), Alessandra Di Gregorio (Collaborator), Simonetta Guarrera (Collaborator), Salvatore Panico (Collaborator), Fulvio Ricceri (Collaborator), Valeria Romanazzi (Collaborator), Carlotta Sacerdote (Collaborator), Paolo Vineis (Collaborator), Inês Barroso (Collaborator), Manjinder S Sandhu (Collaborator), Robert N Luben (Collaborator), Gabriel J Crawford (Collaborator), Pekka Jousilahti (Collaborator), Markus Perola (Collaborator), Michael Boehnke (Collaborator), Lori L Bonnycastle (Collaborator), Francis S Collins (Collaborator), Anne U Jackson (Collaborator), Karen L Mohlke (Collaborator), Heather M Stringham (Collaborator), Timo T Valle (Collaborator), Cristen J Willer (Collaborator), Richard N Bergman (Collaborator), Mario A Morken (Collaborator), Angela Döring (Collaborator), Christian Gieger (Collaborator), Thomas Illig (Collaborator), Thomas Meitinger (Collaborator), Elin Org (Collaborator), Arne Pfeufer (Collaborator), H Erich Wichmann (Collaborator), Sekar Kathiresan (Collaborator), Jaume Marrugat (Collaborator), Christopher J O'Donnell (Collaborator), Stephen M Schwartz (Collaborator), David S Siscovick (Collaborator), Isaac Subirana (Collaborator), Nelson B Freimer (Collaborator), Anna-Liisa Hartikainen (Collaborator), Mark I McCarthy (Collaborator), Paul F OReilly (Collaborator), Leena Peltonen (Collaborator), Anneli Pouta (Collaborator), Paul E de Jong (Collaborator), Harold Snieder (Collaborator), Wiek H van Gilst (Collaborator), Robert Clarke (Collaborator), Anuj Goel (Collaborator), Anders Hamsten (Collaborator), John F Peden (Collaborator), Udo Seedorf (Collaborator), Christine Syv (Collaborator), Giovanni Tognoni (Collaborator), Edward G Lakatta (Collaborator), Serena Sanna (Collaborator), Paul Scheet (Collaborator), David Schlessinger (Collaborator), Angelo Scuteri (Collaborator), Marcus Dörr (Collaborator), Florian Ernst (Collaborator), Stephan B Felix (Collaborator), Georg Homuth (Collaborator), Roberto Lorbeer (Collaborator), Thorsten Reffelmann (Collaborator), Rainer Rettig (Collaborator), Uwe Völker (Collaborator), Pilar Galan (Collaborator), Ivo G Gut (Collaborator), Serge Hercberg (Collaborator), G Mark Lathrop (Collaborator), Diana Zeleneka (Collaborator), Panos Deloukas (Collaborator), Nicole Soranzo (Collaborator), Frances M Williams (Collaborator), Guangju Zhai (Collaborator), Veikko Salomaa (Collaborator), Markku Laakso (Collaborator), Roberto Elosua (Collaborator), Nita G Forouhi (Collaborator), Henry Völzke (Collaborator), Cuno S Uiterwaal (Collaborator), Yvonne T van der Schouw (Collaborator), Mattijs E Numans (Collaborator), Giuseppe Matullo (Collaborator), Gerjan Navis (Collaborator), Göran Berglund (Collaborator), Sheila A Bingham (Collaborator), Jaspal S Kooner (Collaborator), Andrew D Paterson (Collaborator), John M Connell (Collaborator), Stefania Bandinelli (Collaborator), Luigi Ferrucci (Collaborator), Hugh Watkins (Collaborator), Tim D Spector (Collaborator), Jaakko Tuomilehto (Collaborator), David Altshuler (Collaborator), David P Strachan (Collaborator), Maris Laan (Collaborator), Pierre Meneton (Collaborator), Nicholas J Wareham (Collaborator), Manuela Uda (Collaborator), Marjo-Riitta Jarvelin (Collaborator), Vincent Mooser (Collaborator), Olle Melander (Collaborator), Ruth J F Loos (Collaborator), Paul Elliott (Collaborator), Gonçalo R Abecasis (Collaborator), Mark Caulfield (Collaborator), Patricia B Munroe (Collaborator), Tony Attwood (Collaborator), Stephanie Belz (Collaborator), Peter Braund (Collaborator), Jessy Brocheton (Collaborator), François Cambien (Collaborator), Jason Cooper (Collaborator), Abi Crisp-Hihn (Collaborator), Patrick Diemert (Collaborator), Jeanette Eardman (Collaborator), Nicola Foad (Collaborator), Tiphaine Godefroy (Collaborator), Alison H Goodall (Collaborator), Jay Gracey (Collaborator), Emma Gray (Collaborator), Rhian Gwilliams (Collaborator), Susanne Heimer (Collaborator), Christian Hengstenberg (Collaborator), Jennifer Jolley (Collaborator), Unni Krishnan (Collaborator), Heather Lloyd-Jones (Collaborator), Ulrika Liljedahl (Collaborator), Ingrid Lugauer (Collaborator), Per Lundmark (Collaborator), Seraya Maouche (Collaborator), Jasbir S Moore (Collaborator), Gilles Montalescot (Collaborator), David Muir (Collaborator), Elizabeth Murray (Collaborator), Chris P Nelson (Collaborator), Jessica Neudert (Collaborator), David Niblett (Collaborator), Karen O'Leary (Collaborator), Willem H Ouwehand (Collaborator), Helen Pollard (Collaborator), Carole Proust (Collaborator), Angela Rankin (Collaborator), Augusto Rendon (Collaborator), Catherine M Rice (Collaborator), Hendrik B Sager (Collaborator), Jennifer Sambrook (Collaborator), Gerd Schmitz (Collaborator), Michael Scholz (Collaborator), Laura Schroeder (Collaborator), Heribert Schunkert (Collaborator), Jonathan Stephens (Collaborator), Ann-Christine Syvannen (Collaborator), Stefanie Tennstedt (Collaborator)

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	American Journal of Human Genetics
Volume	89
Issue number	6
DOIs	https://doi.org/10.1016/j.ajhg.2011.10.013
Publication status	Published - 9 Dec 2011

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Access to Document

10.1016/j.ajhg.2011.10.013

Cite this

Gaunt, T. R., Padmanabhan, S., Tomaszewski, M., Kumari, M., Morris, R. W., Tzoulaki, I., O'Brien, E. T., Poulter, N. R., Sever, P., Shields, D. C., Thom, S., Wannamethee, S. G., Whincup, P. H., Dobson, R. J., Howard, P. J., Mein, C. A., Onipinla, A., Shaw-Hawkins, S., Zhang, Y., ... Tennstedt, S. (2011). Blood pressure loci identified with a gene-centric array. American Journal of Human Genetics, 89(6). https://doi.org/10.1016/j.ajhg.2011.10.013

@article{9760f5f819bf4374b3c52fe0b5e873ff,

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.",

author = "Gaunt, {Tom R} and Sandosh Padmanabhan and Maciej Tomaszewski and Meena Kumari and Morris, {Richard W} and Ioanna Tzoulaki and O'Brien, {Eoin T} and Poulter, {Neil R} and Peter Sever and Shields, {Denis C} and Simon Thom and Wannamethee, {Sasiwarang G} and Whincup, {Peter H} and Dobson, {Richard J} and Howard, {Philip J} and Mein, {Charles A} and Abiodun Onipinla and Sue Shaw-Hawkins and Yun Zhang and {Davey Smith}, George and Day, {Ian N M} and Lawlor, {Debbie A} and Fowkes, {F Gerald} and Nelson, {Christopher P} and Nicola Glorioso and Hani Neuvrith and Erika Salvi and Staessen, {Jan A} and Andrea Stucchi and Nabila Devos and Xavier Jeunemaitre and Pierre-Fran{\c c}ois Plouin and Jean Tichet and Peeter Juhanson and Margus Putku and Siim S{\~o}ber and Gudrun Veldre and Margus Viigimaa and Anna Levinsson and Annika Rosengren and Thelle, {Dag S} and Hastie, {Claire E} and Thomas Hedner and Lee, {Wai K} and Bj{\"o}rn Wahlstrand and Rebecca Hardy and Andrew Wong and Cooper, {Jackie A} and Jutta Palmen and Li Chen and Stewart, {Alexandre F R} and Wells, {George A} and Harm-Jan Westra and Wolfs, {Marcel G M} and Franzosi, {Maria Grazia} and Mark Lathrop and Juan-Pablo Casas and Fotios Drenos and Holmes, {Michael V} and Mika Kivimaki and Sonia Shah and Tina Shah and Talmud, {Philippa J} and John Whittaker and Christian Delles and Diana Kuh and Humphries, {Steve E} and Fredrik Nyberg and Daniele Cusi and Robert Roberts and Lude Franke and Stanton, {Alice V} and Hingorani, {Aroon D} and Christopher Newton-Cheh and Toby Johnson and Vesela Gateva and Tobin, {Martin D} and Murielle Bochud and Lachlan Coin and Najjar, {Samer S} and Jing Hua and Heath, {Simon C} and Susana Eyheramendy and Konstantinos Papadakis and Voight, {Benjamin F} and Scott, {Laura J} and Feng Zhang and Martin Farrall and Toshiko Tanaka and Chris Wallace and Chambers, {John C} and Kay-Tee Khaw and Peter Nilsson and {van der Harst}, Pim and Silvia Polidoro and Grobbee, {Diederick E} and Onland-Moret, {N Charlotte} and Bots, {Michiel L} and Wain, {Louise V} and Elliott, {Katherine S} and Alexander Teumer and Jian'an Luan and Gavin Lucas and Johanna Kuusisto and Burton, {Paul R} and David Hadley and McArdle, {Wendy L} and {Wellcome Trust Case Control Consortium}, {I-chip For Psoriasis} and Morris Brown and Anna Dominiczak and Newhouse, {Stephen J} and Samani, {Nilesh J} and John Webster and Eleftheria Zeggini and Beckmann, {Jacques S} and Sven Bergmann and Noha Lim and Kijoung Song and Peter Vollenweider and Gerard Waeber and Waterworth, {Dawn M} and Xin Yuan and Leif Groop and Marju Orho and Alessandra Allione and {Di Gregorio}, Alessandra and Simonetta Guarrera and Salvatore Panico and Fulvio Ricceri and Valeria Romanazzi and Carlotta Sacerdote and Paolo Vineis and In{\^e}s Barroso and Sandhu, {Manjinder S} and Luben, {Robert N} and Crawford, {Gabriel J} and Pekka Jousilahti and Markus Perola and Michael Boehnke and Bonnycastle, {Lori L} and Collins, {Francis S} and Jackson, {Anne U} and Mohlke, {Karen L} and Stringham, {Heather M} and Valle, {Timo T} and Willer, {Cristen J} and Bergman, {Richard N} and Morken, {Mario A} and Angela D{\"o}ring and Christian Gieger and Thomas Illig and Thomas Meitinger and Elin Org and Arne Pfeufer and Wichmann, {H Erich} and Sekar Kathiresan and Jaume Marrugat and O'Donnell, {Christopher J} and Schwartz, {Stephen M} and Siscovick, {David S} and Isaac Subirana and Freimer, {Nelson B} and Anna-Liisa Hartikainen and McCarthy, {Mark I} and OReilly, {Paul F} and Leena Peltonen and Anneli Pouta and {de Jong}, {Paul E} and Harold Snieder and {van Gilst}, {Wiek H} and Robert Clarke and Anuj Goel and Anders Hamsten and Peden, {John F} and Udo Seedorf and Christine Syv and Giovanni Tognoni and Lakatta, {Edward G} and Serena Sanna and Paul Scheet and David Schlessinger and Angelo Scuteri and Marcus D{\"o}rr and Florian Ernst and Felix, {Stephan B} and Georg Homuth and Roberto Lorbeer and Thorsten Reffelmann and Rainer Rettig and Uwe V{\"o}lker and Pilar Galan and Gut, {Ivo G} and Serge Hercberg and Lathrop, {G Mark} and Diana Zeleneka and Panos Deloukas and Nicole Soranzo and Williams, {Frances M} and Guangju Zhai and Veikko Salomaa and Markku Laakso and Roberto Elosua and Forouhi, {Nita G} and Henry V{\"o}lzke and Uiterwaal, {Cuno S} and {van der Schouw}, {Yvonne T} and Numans, {Mattijs E} and Giuseppe Matullo and Gerjan Navis and G{\"o}ran Berglund and Bingham, {Sheila A} and Kooner, {Jaspal S} and Paterson, {Andrew D} and Connell, {John M} and Stefania Bandinelli and Luigi Ferrucci and Hugh Watkins and Spector, {Tim D} and Jaakko Tuomilehto and David Altshuler and Strachan, {David P} and Maris Laan and Pierre Meneton and Wareham, {Nicholas J} and Manuela Uda and Marjo-Riitta Jarvelin and Vincent Mooser and Olle Melander and Loos, {Ruth J F} and Paul Elliott and Abecasis, {Gon{\c c}alo R} and Mark Caulfield and Munroe, {Patricia B} and Tony Attwood and Stephanie Belz and Peter Braund and Jessy Brocheton and Fran{\c c}ois Cambien and Jason Cooper and Abi Crisp-Hihn and Patrick Diemert and Jeanette Eardman and Nicola Foad and Tiphaine Godefroy and Goodall, {Alison H} and Jay Gracey and Emma Gray and Rhian Gwilliams and Susanne Heimer and Christian Hengstenberg and Jennifer Jolley and Unni Krishnan and Heather Lloyd-Jones and Ulrika Liljedahl and Ingrid Lugauer and Per Lundmark and Seraya Maouche and Moore, {Jasbir S} and Gilles Montalescot and David Muir and Elizabeth Murray and Nelson, {Chris P} and Jessica Neudert and David Niblett and Karen O'Leary and Ouwehand, {Willem H} and Helen Pollard and Carole Proust and Angela Rankin and Augusto Rendon and Rice, {Catherine M} and Sager, {Hendrik B} and Jennifer Sambrook and Gerd Schmitz and Michael Scholz and Laura Schroeder and Heribert Schunkert and Jonathan Stephens and Ann-Christine Syvannen and Stefanie Tennstedt",

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year = "2011",

month = dec,

day = "9",

doi = "10.1016/j.ajhg.2011.10.013",

language = "English",

volume = "89",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "6",

}

Gaunt, TR, Padmanabhan, S, Tomaszewski, M, Kumari, M, Morris, RW, Tzoulaki, I, O'Brien, ET, Poulter, NR, Sever, P, Shields, DC, Thom, S, Wannamethee, SG, Whincup, PH, Dobson, RJ, Howard, PJ, Mein, CA, Onipinla, A, Shaw-Hawkins, S, Zhang, Y, Davey Smith, G, Day, INM, Lawlor, DA, Fowkes, FG, Nelson, CP, Glorioso, N, Neuvrith, H, Salvi, E, Staessen, JA, Stucchi, A, Devos, N, Jeunemaitre, X, Plouin, P-F, Tichet, J, Juhanson, P, Putku, M, Sõber, S, Veldre, G, Viigimaa, M, Levinsson, A, Rosengren, A, Thelle, DS, Hastie, CE, Hedner, T, Lee, WK, Wahlstrand, B, Hardy, R, Wong, A, Cooper, JA, Palmen, J, Chen, L, Stewart, AFR, Wells, GA, Westra, H-J, Wolfs, MGM, Franzosi, MG, Lathrop, M, Casas, J-P, Drenos, F, Holmes, MV, Kivimaki, M, Shah, S, Shah, T, Talmud, PJ, Whittaker, J, Delles, C, Kuh, D, Humphries, SE, Nyberg, F, Cusi, D, Roberts, R, Franke, L, Stanton, AV, Hingorani, AD, Newton-Cheh, C, Johnson, T, Gateva, V, Tobin, MD, Bochud, M, Coin, L, Najjar, SS, Hua, J, Heath, SC, Eyheramendy, S, Papadakis, K, Voight, BF, Scott, LJ, Zhang, F, Farrall, M, Tanaka, T, Wallace, C, Chambers, JC, Khaw, K-T, Nilsson, P, van der Harst, P, Polidoro, S, Grobbee, DE, Onland-Moret, NC, Bots, ML, Wain, LV, Elliott, KS, Teumer, A, Luan, J, Lucas, G, Kuusisto, J, Burton, PR, Hadley, D, McArdle, WL, Wellcome Trust Case Control Consortium, IFP, Brown, M, Dominiczak, A, Newhouse, SJ, Samani, NJ, Webster, J, Zeggini, E, Beckmann, JS, Bergmann, S, Lim, N, Song, K, Vollenweider, P, Waeber, G, Waterworth, DM, Yuan, X, Groop, L, Orho, M, Allione, A, Di Gregorio, A, Guarrera, S, Panico, S, Ricceri, F, Romanazzi, V, Sacerdote, C, Vineis, P, Barroso, I, Sandhu, MS, Luben, RN, Crawford, GJ, Jousilahti, P, Perola, M, Boehnke, M, Bonnycastle, LL, Collins, FS, Jackson, AU, Mohlke, KL, Stringham, HM, Valle, TT, Willer, CJ, Bergman, RN, Morken, MA, Döring, A, Gieger, C, Illig, T, Meitinger, T, Org, E, Pfeufer, A, Wichmann, HE, Kathiresan, S, Marrugat, J, O'Donnell, CJ, Schwartz, SM, Siscovick, DS, Subirana, I, Freimer, NB, Hartikainen, A-L, McCarthy, MI, OReilly, PF, Peltonen, L, Pouta, A, de Jong, PE, Snieder, H, van Gilst, WH, Clarke, R, Goel, A, Hamsten, A, Peden, JF, Seedorf, U, Syv, C, Tognoni, G, Lakatta, EG, Sanna, S, Scheet, P, Schlessinger, D, Scuteri, A, Dörr, M, Ernst, F, Felix, SB, Homuth, G, Lorbeer, R, Reffelmann, T, Rettig, R, Völker, U, Galan, P, Gut, IG, Hercberg, S, Lathrop, GM, Zeleneka, D, Deloukas, P, Soranzo, N, Williams, FM, Zhai, G, Salomaa, V, Laakso, M, Elosua, R, Forouhi, NG, Völzke, H, Uiterwaal, CS, van der Schouw, YT, Numans, ME, Matullo, G, Navis, G, Berglund, G, Bingham, SA, Kooner, JS, Paterson, AD, Connell, JM, Bandinelli, S, Ferrucci, L, Watkins, H, Spector, TD, Tuomilehto, J, Altshuler, D, Strachan, DP, Laan, M, Meneton, P, Wareham, NJ, Uda, M, Jarvelin, M-R, Mooser, V, Melander, O, Loos, RJF, Elliott, P, Abecasis, GR, Caulfield, M, Munroe, PB, Attwood, T, Belz, S, Braund, P, Brocheton, J, Cambien, F, Cooper, J, Crisp-Hihn, A, Diemert, P, Eardman, J, Foad, N, Godefroy, T, Goodall, AH, Gracey, J, Gray, E, Gwilliams, R, Heimer, S, Hengstenberg, C, Jolley, J, Krishnan, U, Lloyd-Jones, H, Liljedahl, U, Lugauer, I, Lundmark, P, Maouche, S, Moore, JS, Montalescot, G, Muir, D, Murray, E, Nelson, CP, Neudert, J, Niblett, D, O'Leary, K, Ouwehand, WH, Pollard, H, Proust, C, Rankin, A, Rendon, A, Rice, CM, Sager, HB, Sambrook, J, Schmitz, G, Scholz, M, Schroeder, L, Schunkert, H, Stephens, J, Syvannen, A-C & Tennstedt, S 2011, 'Blood pressure loci identified with a gene-centric array.', American Journal of Human Genetics, vol. 89, no. 6. https://doi.org/10.1016/j.ajhg.2011.10.013

TY - JOUR

T1 - Blood pressure loci identified with a gene-centric array.

AU - Gaunt, Tom R

AU - Padmanabhan, Sandosh

AU - Tomaszewski, Maciej

AU - Kumari, Meena

AU - Morris, Richard W

AU - Tzoulaki, Ioanna

AU - O'Brien, Eoin T

AU - Poulter, Neil R

AU - Sever, Peter

AU - Shields, Denis C

AU - Thom, Simon

AU - Wannamethee, Sasiwarang G

AU - Whincup, Peter H

AU - Dobson, Richard J

AU - Howard, Philip J

AU - Mein, Charles A

AU - Onipinla, Abiodun

AU - Shaw-Hawkins, Sue

AU - Zhang, Yun

AU - Davey Smith, George

AU - Day, Ian N M

AU - Lawlor, Debbie A

AU - Fowkes, F Gerald

AU - Nelson, Christopher P

AU - Glorioso, Nicola

AU - Neuvrith, Hani

AU - Salvi, Erika

AU - Staessen, Jan A

AU - Stucchi, Andrea

AU - Devos, Nabila

AU - Jeunemaitre, Xavier

AU - Plouin, Pierre-François

AU - Tichet, Jean

AU - Juhanson, Peeter

AU - Putku, Margus

AU - Sõber, Siim

AU - Veldre, Gudrun

AU - Viigimaa, Margus

AU - Levinsson, Anna

AU - Rosengren, Annika

AU - Thelle, Dag S

AU - Hastie, Claire E

AU - Hedner, Thomas

AU - Lee, Wai K

AU - Wahlstrand, Björn

AU - Hardy, Rebecca

AU - Wong, Andrew

AU - Cooper, Jackie A

AU - Palmen, Jutta

AU - Chen, Li

AU - Stewart, Alexandre F R

AU - Wells, George A

AU - Westra, Harm-Jan

AU - Wolfs, Marcel G M

AU - Franzosi, Maria Grazia

AU - Lathrop, Mark

AU - Casas, Juan-Pablo

AU - Drenos, Fotios

AU - Holmes, Michael V

AU - Kivimaki, Mika

AU - Shah, Sonia

AU - Shah, Tina

AU - Talmud, Philippa J

AU - Whittaker, John

AU - Delles, Christian

AU - Kuh, Diana

AU - Humphries, Steve E

AU - Nyberg, Fredrik

AU - Cusi, Daniele

AU - Roberts, Robert

AU - Franke, Lude

AU - Stanton, Alice V

AU - Hingorani, Aroon D

A2 - Newton-Cheh, Christopher

A2 - Johnson, Toby

A2 - Gateva, Vesela

A2 - Tobin, Martin D

A2 - Bochud, Murielle

A2 - Coin, Lachlan

A2 - Najjar, Samer S

A2 - Hua, Jing

A2 - Heath, Simon C

A2 - Eyheramendy, Susana

A2 - Papadakis, Konstantinos

A2 - Voight, Benjamin F

A2 - Scott, Laura J

A2 - Zhang, Feng

A2 - Farrall, Martin

A2 - Tanaka, Toshiko

A2 - Wallace, Chris

A2 - Chambers, John C

A2 - Khaw, Kay-Tee

A2 - Nilsson, Peter

A2 - van der Harst, Pim

A2 - Polidoro, Silvia

A2 - Grobbee, Diederick E

A2 - Onland-Moret, N Charlotte

A2 - Bots, Michiel L

A2 - Wain, Louise V

A2 - Elliott, Katherine S

A2 - Teumer, Alexander

A2 - Luan, Jian'an

A2 - Lucas, Gavin

A2 - Kuusisto, Johanna

A2 - Burton, Paul R

A2 - Hadley, David

A2 - McArdle, Wendy L

A2 - Wellcome Trust Case Control Consortium, I-chip For Psoriasis

A2 - Brown, Morris

A2 - Dominiczak, Anna

A2 - Newhouse, Stephen J

A2 - Samani, Nilesh J

A2 - Webster, John

A2 - Zeggini, Eleftheria

A2 - Beckmann, Jacques S

A2 - Bergmann, Sven

A2 - Lim, Noha

A2 - Song, Kijoung

A2 - Vollenweider, Peter

A2 - Waeber, Gerard

A2 - Waterworth, Dawn M

A2 - Yuan, Xin

A2 - Groop, Leif

A2 - Orho, Marju

A2 - Allione, Alessandra

A2 - Di Gregorio, Alessandra

A2 - Guarrera, Simonetta

A2 - Panico, Salvatore

A2 - Ricceri, Fulvio

A2 - Romanazzi, Valeria

A2 - Sacerdote, Carlotta

A2 - Vineis, Paolo

A2 - Barroso, Inês

A2 - Sandhu, Manjinder S

A2 - Luben, Robert N

A2 - Crawford, Gabriel J

A2 - Jousilahti, Pekka

A2 - Perola, Markus

A2 - Boehnke, Michael

A2 - Bonnycastle, Lori L

A2 - Collins, Francis S

A2 - Jackson, Anne U

A2 - Mohlke, Karen L

A2 - Stringham, Heather M

A2 - Valle, Timo T

A2 - Willer, Cristen J

A2 - Bergman, Richard N

A2 - Morken, Mario A

A2 - Döring, Angela

A2 - Gieger, Christian

A2 - Illig, Thomas

A2 - Meitinger, Thomas

A2 - Org, Elin

A2 - Pfeufer, Arne

A2 - Wichmann, H Erich

A2 - Kathiresan, Sekar

A2 - Marrugat, Jaume

A2 - O'Donnell, Christopher J

A2 - Schwartz, Stephen M

A2 - Siscovick, David S

A2 - Subirana, Isaac

A2 - Freimer, Nelson B

A2 - Hartikainen, Anna-Liisa

A2 - McCarthy, Mark I

A2 - OReilly, Paul F

A2 - Peltonen, Leena

A2 - Pouta, Anneli

A2 - de Jong, Paul E

A2 - Snieder, Harold

A2 - van Gilst, Wiek H

A2 - Clarke, Robert

A2 - Goel, Anuj

A2 - Hamsten, Anders

A2 - Peden, John F

A2 - Seedorf, Udo

A2 - Syv, Christine

A2 - Tognoni, Giovanni

A2 - Lakatta, Edward G

A2 - Sanna, Serena

A2 - Scheet, Paul

A2 - Schlessinger, David

A2 - Scuteri, Angelo

A2 - Dörr, Marcus

A2 - Ernst, Florian

A2 - Felix, Stephan B

A2 - Homuth, Georg

A2 - Lorbeer, Roberto

A2 - Reffelmann, Thorsten

A2 - Rettig, Rainer

A2 - Völker, Uwe

A2 - Galan, Pilar

A2 - Gut, Ivo G

A2 - Hercberg, Serge

A2 - Lathrop, G Mark

A2 - Zeleneka, Diana

A2 - Deloukas, Panos

A2 - Soranzo, Nicole

A2 - Williams, Frances M

A2 - Zhai, Guangju

A2 - Salomaa, Veikko

A2 - Laakso, Markku

A2 - Elosua, Roberto

A2 - Forouhi, Nita G

A2 - Völzke, Henry

A2 - Uiterwaal, Cuno S

A2 - van der Schouw, Yvonne T

A2 - Numans, Mattijs E

A2 - Matullo, Giuseppe

A2 - Navis, Gerjan

A2 - Berglund, Göran

A2 - Bingham, Sheila A

A2 - Kooner, Jaspal S

A2 - Paterson, Andrew D

A2 - Connell, John M

A2 - Bandinelli, Stefania

A2 - Ferrucci, Luigi

A2 - Watkins, Hugh

A2 - Spector, Tim D

A2 - Tuomilehto, Jaakko

A2 - Altshuler, David

A2 - Strachan, David P

A2 - Laan, Maris

A2 - Meneton, Pierre

A2 - Wareham, Nicholas J

A2 - Uda, Manuela

A2 - Jarvelin, Marjo-Riitta

A2 - Mooser, Vincent

A2 - Melander, Olle

A2 - Loos, Ruth J F

A2 - Elliott, Paul

A2 - Abecasis, Gonçalo R

A2 - Caulfield, Mark

A2 - Munroe, Patricia B

A2 - Attwood, Tony

A2 - Belz, Stephanie

A2 - Braund, Peter

A2 - Brocheton, Jessy

A2 - Cambien, François

A2 - Cooper, Jason

A2 - Crisp-Hihn, Abi

A2 - Diemert, Patrick

A2 - Eardman, Jeanette

A2 - Foad, Nicola

A2 - Godefroy, Tiphaine

A2 - Goodall, Alison H

A2 - Gracey, Jay

A2 - Gray, Emma

A2 - Gwilliams, Rhian

A2 - Heimer, Susanne

A2 - Hengstenberg, Christian

A2 - Jolley, Jennifer

A2 - Krishnan, Unni

A2 - Lloyd-Jones, Heather

A2 - Liljedahl, Ulrika

A2 - Lugauer, Ingrid

A2 - Lundmark, Per

A2 - Maouche, Seraya

A2 - Moore, Jasbir S

A2 - Montalescot, Gilles

A2 - Muir, David

A2 - Murray, Elizabeth

A2 - Nelson, Chris P

A2 - Neudert, Jessica

A2 - Niblett, David

A2 - O'Leary, Karen

A2 - Ouwehand, Willem H

A2 - Pollard, Helen

A2 - Proust, Carole

A2 - Rankin, Angela

A2 - Rendon, Augusto

A2 - Rice, Catherine M

A2 - Sager, Hendrik B

A2 - Sambrook, Jennifer

A2 - Schmitz, Gerd

A2 - Scholz, Michael

A2 - Schroeder, Laura

A2 - Schunkert, Heribert

A2 - Stephens, Jonathan

A2 - Syvannen, Ann-Christine

A2 - Tennstedt, Stefanie

N1 - 070191/Z/03/A, Wellcome Trust, United Kingdom070191/Z/03/Z, Wellcome Trust, United Kingdom076113/C/04/Z, Wellcome Trust, United Kingdom090532, Wellcome Trust, United Kingdom093078/Z/10/Z, Wellcome Trust, United KingdomAG13196, NIA NIH HHS, United StatesCH/98001, British Heart Foundation, United KingdomFS05/125, British Heart Foundation, United KingdomG0100222, Medical Research Council, United KingdomG0400874, Medical Research Council, United KingdomG0401527, Medical Research Council, United KingdomG0501942, Medical Research Council, United KingdomG0701863, Medical Research Council, United KingdomG0801056, Medical Research Council, United KingdomG0802432, Medical Research Council, United KingdomG0902037, Medical Research Council, United KingdomG1000143, Medical Research Council, United KingdomG19/35, Medical Research Council, United KingdomG8802774, Medical Research Council, United KingdomG9521010, Medical Research Council, United KingdomG9521010D, Medical Research Council, United KingdomHS06516, AHRQ HHS, United StatesMC_U106179471, Medical Research Council, United KingdomMC_U123092720, Medical Research Council, United KingdomMC_U123092723, Medical Research Council, United KingdomMC_U137686857, Medical Research Council, United KingdomMC_UP_A100_1003, Medical Research Council, United KingdomMOP172605, Canadian Institutes of Health Research, CanadaMOP77682, Canadian Institutes of Health Research, CanadaMOP82810, Canadian Institutes of Health Research, CanadaPG/07/131/24254, British Heart Foundation, United KingdomPG/07/132/24256, British Heart Foundation, United KingdomPG/07/133/24260, British Heart Foundation, United KingdomPG/97012, British Heart Foundation, United KingdomR01 AG017644-09S1, NIA NIH HHS, United StatesRG/07/005/23633, British Heart Foundation, United KingdomRG/07/008/23674, British Heart Foundation, United KingdomRG/08/008, British Heart Foundation, United KingdomRG/08/008/25291, British Heart Foundation, United KingdomRG/08/013/25942, British Heart Foundation, United KingdomRG/2001004, British Heart Foundation, United KingdomSP/07/007/2367, British Heart Foundation, United KingdomSP/08/005/25115, British Heart Foundation, United Kingdom, Department of Health, United Kingdom

PY - 2011/12/9

Y1 - 2011/12/9

N2 - 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.

AB - 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.

U2 - 10.1016/j.ajhg.2011.10.013

DO - 10.1016/j.ajhg.2011.10.013

M3 - Article

C2 - 22100073

SN - 0002-9297

VL - 89

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -

Blood pressure loci identified with a gene-centric array.

Abstract

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