Blood pressure loci identified with a gene-centric array

Toby Johnson; Tom R. Gaunt; Stephen J. Newhouse; 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; Morris J. Brown; John M. Connell; 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; Alison H. Goodall; F. Gerald Fowkes; Gonalo R. Abecasis; Paul Elliott; Vesela Gateva; Peter S. Braund; Paul R. Burton; Christopher P. Nelson; Martin D. Tobin; Pim Van Der Harst; Nicola Glorioso; Hani Neuvrith; Erika Salvi; Jan A. Staessen; Andrea Stucchi; Nabila Devos; Xavier Jeunemaitre; Pierre Franois Plouin; Jean Tichet; Peeter Juhanson; Elin Org; Margus Putku; Siim Sõber; Gudrun Veldre; Margus Viigimaa; Anna Levinsson; Annika Rosengren; Dag S. Thelle; Claire E. Hastie; Thomas Hedner; Wai K. Lee; Olle Melander; 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; Robert Clarke; Maria Grazia Franzosi; Anuj Goel; Anders Hamsten; Mark Lathrop; John F. Peden; Udo Seedorf; Hugh Watkins; Willem H. Ouwehand; Jennifer Sambrook; Jonathan Stephens; Juan Pablo Casas; Fotios Drenos; Michael V. Holmes; Mika Kivimaki; Sonia Shah; Tina Shah; Philippa J. Talmud; John Whittaker; Chris Wallace; Christian Delles; Maris Laan; Diana Kuh; Steve E. Humphries; Fredrik Nyberg; Daniele Cusi; Robert Roberts; Christopher Newton-Cheh; Lude Franke; Alice V. Stanton; Anna F. Dominiczak; Martin Farrall; Aroon D. Hingorani; Nilesh J. Samani; Mark J. Caulfield; Patricia B. Munroe

doi:10.1016/j.ajhg.2011.10.013

Blood pressure loci identified with a gene-centric array

Toby Johnson^*, Tom R. Gaunt, Stephen J. Newhouse, 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, Morris J. Brown, John M. Connell, Richard J. Dobson, Philip J. Howard, Charles A. MeinAbiodun Onipinla, Sue Shaw-Hawkins, Yun Zhang, George Davey Smith, Ian N.M. Day, Debbie A. Lawlor, Alison H. Goodall, F. Gerald Fowkes, Gonalo R. Abecasis, Paul Elliott, Vesela Gateva, Peter S. Braund, Paul R. Burton, Christopher P. Nelson, Martin D. Tobin, Pim Van Der Harst, Nicola Glorioso, Hani Neuvrith, Erika Salvi, Jan A. Staessen, Andrea Stucchi, Nabila Devos, Xavier Jeunemaitre, Pierre Franois Plouin, Jean Tichet, Peeter Juhanson, Elin Org, Margus Putku, Siim Sõber, Gudrun Veldre, Margus Viigimaa, Anna Levinsson, Annika Rosengren, Dag S. Thelle, Claire E. Hastie, Thomas Hedner, Wai K. Lee, Olle Melander, 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, Robert Clarke, Maria Grazia Franzosi, Anuj Goel, Anders Hamsten, Mark Lathrop, John F. Peden, Udo Seedorf, Hugh Watkins, Willem H. Ouwehand, Jennifer Sambrook, Jonathan Stephens, Juan Pablo Casas, Fotios Drenos, Michael V. Holmes, Mika Kivimaki, Sonia Shah, Tina Shah, Philippa J. Talmud, John Whittaker, Chris Wallace, Christian Delles, Maris Laan, Diana Kuh, Steve E. Humphries, Fredrik Nyberg, Daniele Cusi, Robert Roberts, Christopher Newton-Cheh, Lude Franke, Alice V. Stanton, Anna F. Dominiczak, Martin Farrall, Aroon D. Hingorani, Nilesh J. Samani, Mark J. Caulfield, Patricia B. Munroe

^*Corresponding author for this work

105 Citations (Scopus)

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
Pages (from-to)	688-700
Number of pages	13
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2011.10.013
Publication status	Published - 09.12.2011
Externally published	Yes

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10.1016/j.ajhg.2011.10.013

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Johnson, T., Gaunt, T. R., Newhouse, S. J., 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., Brown, M. J., Connell, J. M., Dobson, R. J., Howard, P. J., ... Munroe, P. B. (2011). Blood pressure loci identified with a gene-centric array. American Journal of Human Genetics, 89(6), 688-700. https://doi.org/10.1016/j.ajhg.2011.10.013

@article{28d40edccf1f4cacbb9736c5c308a810,

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 = "Toby Johnson and Gaunt, {Tom R.} and Newhouse, {Stephen J.} 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 Brown, {Morris J.} and Connell, {John M.} and Dobson, {Richard J.} and Howard, {Philip J.} and Mein, {Charles A.} and Abiodun Onipinla and Sue Shaw-Hawkins and Yun Zhang and Smith, {George Davey} and Day, {Ian N.M.} and Lawlor, {Debbie A.} and Goodall, {Alison H.} and Fowkes, {F. Gerald} and Abecasis, {Gonalo R.} and Paul Elliott and Vesela Gateva and Braund, {Peter S.} and Burton, {Paul R.} and Nelson, {Christopher P.} and Tobin, {Martin D.} and {Van Der Harst}, Pim and Nicola Glorioso and Hani Neuvrith and Erika Salvi and Staessen, {Jan A.} and Andrea Stucchi and Nabila Devos and Xavier Jeunemaitre and Plouin, {Pierre Franois} and Jean Tichet and Peeter Juhanson and Elin Org 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 Olle Melander 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 Westra, {Harm Jan} and Wolfs, {Marcel G.M.} and Robert Clarke and Franzosi, {Maria Grazia} and Anuj Goel and Anders Hamsten and Mark Lathrop and Peden, {John F.} and Udo Seedorf and Hugh Watkins and Ouwehand, {Willem H.} and Jennifer Sambrook and Jonathan Stephens and Casas, {Juan Pablo} and Fotios Drenos and Holmes, {Michael V.} and Mika Kivimaki and Sonia Shah and Tina Shah and Talmud, {Philippa J.} and John Whittaker and Chris Wallace and Christian Delles and Maris Laan and Diana Kuh and Humphries, {Steve E.} and Fredrik Nyberg and Daniele Cusi and Robert Roberts and Christopher Newton-Cheh and Lude Franke and Stanton, {Alice V.} and Dominiczak, {Anna F.} and Martin Farrall and Hingorani, {Aroon D.} and Samani, {Nilesh J.} and Caulfield, {Mark J.} and Munroe, {Patricia B.}",

year = "2011",

month = dec,

day = "9",

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

language = "English",

volume = "89",

pages = "688--700",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

number = "6",

}

Johnson, T, Gaunt, TR, Newhouse, SJ, 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, Brown, MJ, Connell, JM, Dobson, RJ, Howard, PJ, Mein, CA, Onipinla, A, Shaw-Hawkins, S, Zhang, Y, Smith, GD, Day, INM, Lawlor, DA, Goodall, AH, Fowkes, FG, Abecasis, GR, Elliott, P, Gateva, V, Braund, PS, Burton, PR, Nelson, CP, Tobin, MD, Van Der Harst, P, Glorioso, N, Neuvrith, H, Salvi, E, Staessen, JA, Stucchi, A, Devos, N, Jeunemaitre, X, Plouin, PF, Tichet, J, Juhanson, P, Org, E, Putku, M, Sõber, S, Veldre, G, Viigimaa, M, Levinsson, A, Rosengren, A, Thelle, DS, Hastie, CE, Hedner, T, Lee, WK, Melander, O, Wahlstrand, B, Hardy, R, Wong, A, Cooper, JA, Palmen, J, Chen, L, Stewart, AFR, Wells, GA, Westra, HJ, Wolfs, MGM, Clarke, R, Franzosi, MG, Goel, A, Hamsten, A, Lathrop, M, Peden, JF, Seedorf, U, Watkins, H, Ouwehand, WH, Sambrook, J, Stephens, J, Casas, JP, Drenos, F, Holmes, MV, Kivimaki, M, Shah, S, Shah, T, Talmud, PJ, Whittaker, J, Wallace, C, Delles, C, Laan, M, Kuh, D, Humphries, SE, Nyberg, F, Cusi, D, Roberts, R, Newton-Cheh, C, Franke, L, Stanton, AV, Dominiczak, AF, Farrall, M, Hingorani, AD, Samani, NJ, Caulfield, MJ & Munroe, PB 2011, 'Blood pressure loci identified with a gene-centric array', American Journal of Human Genetics, vol. 89, no. 6, pp. 688-700. https://doi.org/10.1016/j.ajhg.2011.10.013

TY - JOUR

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

AU - Johnson, Toby

AU - Gaunt, Tom R.

AU - Newhouse, Stephen J.

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 - Brown, Morris J.

AU - Connell, John M.

AU - Dobson, Richard J.

AU - Howard, Philip J.

AU - Mein, Charles A.

AU - Onipinla, Abiodun

AU - Shaw-Hawkins, Sue

AU - Zhang, Yun

AU - Smith, George Davey

AU - Day, Ian N.M.

AU - Lawlor, Debbie A.

AU - Goodall, Alison H.

AU - Fowkes, F. Gerald

AU - Abecasis, Gonalo R.

AU - Elliott, Paul

AU - Gateva, Vesela

AU - Braund, Peter S.

AU - Burton, Paul R.

AU - Nelson, Christopher P.

AU - Tobin, Martin D.

AU - Van Der Harst, Pim

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 Franois

AU - Tichet, Jean

AU - Juhanson, Peeter

AU - Org, Elin

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 - Melander, Olle

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 - Clarke, Robert

AU - Franzosi, Maria Grazia

AU - Goel, Anuj

AU - Hamsten, Anders

AU - Lathrop, Mark

AU - Peden, John F.

AU - Seedorf, Udo

AU - Watkins, Hugh

AU - Ouwehand, Willem H.

AU - Sambrook, Jennifer

AU - Stephens, Jonathan

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 - Wallace, Chris

AU - Delles, Christian

AU - Laan, Maris

AU - Kuh, Diana

AU - Humphries, Steve E.

AU - Nyberg, Fredrik

AU - Cusi, Daniele

AU - Roberts, Robert

AU - Newton-Cheh, Christopher

AU - Franke, Lude

AU - Stanton, Alice V.

AU - Dominiczak, Anna F.

AU - Farrall, Martin

AU - Hingorani, Aroon D.

AU - Samani, Nilesh J.

AU - Caulfield, Mark J.

AU - Munroe, Patricia B.

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.

UR - http://www.scopus.com/inward/record.url?scp=83555162484&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2011.10.013

DO - 10.1016/j.ajhg.2011.10.013

M3 - Journal articles

C2 - 22100073

AN - SCOPUS:83555162484

SN - 0002-9297

VL - 89

SP - 688

EP - 700

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -

Blood pressure loci identified with a gene-centric array

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