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; Goncalo 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-Francois Plouin; Jean Tichet; Peeter Juhanson; Elin Org; Margus Putku; Siim Sober; Gudrun Veldre; Global BPgen Consortium, Cardiogenics Consortium

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, Goncalo 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-Francois Plouin, Jean Tichet, Peeter Juhanson, Elin Org, Margus Putku, Siim Sober, Gudrun Veldre, Global BPgen Consortium, Cardiogenics Consortium

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

143 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 x 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 x 10(-7) at four further loci (NPR3, FIFE, 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
Pages (from-to)	688-700
Number of pages	13
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

Keywords

GENOME-WIDE ASSOCIATION
QUANTITATIVE-TRAIT LOCI
ESSENTIAL-HYPERTENSION
CARDIOVASCULAR-DISEASE
LINKAGE DISEQUILIBRIUM
SUSCEPTIBILITY LOCI
COMMON VARIANTS
ANGIOTENSINOGEN
METAANALYSIS
POPULATION

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ajhg.2011.10.013

Cite this

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., ... Global BPgen Consortium, Cardiogenics Consortium (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{9e07f9f80a9b4d399a24123ef5d47837,

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 x 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 x 10(-7) at four further loci (NPR3, FIFE, 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.",

keywords = "GENOME-WIDE ASSOCIATION, QUANTITATIVE-TRAIT LOCI, ESSENTIAL-HYPERTENSION, CARDIOVASCULAR-DISEASE, LINKAGE DISEQUILIBRIUM, SUSCEPTIBILITY LOCI, COMMON VARIANTS, ANGIOTENSINOGEN, METAANALYSIS, POPULATION",

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, {Goncalo 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 Pierre-Francois Plouin and Jean Tichet and Peeter Juhanson and Elin Org and Margus Putku and Siim Sober and Gudrun Veldre and {Global BPgen Consortium, Cardiogenics Consortium}",

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",

publisher = "Cell Press",

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, P-F, Tichet, J, Juhanson, P, Org, E, Putku, M, Sober, S, Veldre, G & Global BPgen Consortium, Cardiogenics Consortium 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, Goncalo 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-Francois

AU - Tichet, Jean

AU - Juhanson, Peeter

AU - Org, Elin

AU - Putku, Margus

AU - Sober, Siim

AU - Veldre, Gudrun

AU - Global BPgen Consortium, Cardiogenics Consortium

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 x 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 x 10(-7) at four further loci (NPR3, FIFE, 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 x 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 x 10(-7) at four further loci (NPR3, FIFE, 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.

KW - GENOME-WIDE ASSOCIATION

KW - QUANTITATIVE-TRAIT LOCI

KW - ESSENTIAL-HYPERTENSION

KW - CARDIOVASCULAR-DISEASE

KW - LINKAGE DISEQUILIBRIUM

KW - SUSCEPTIBILITY LOCI

KW - COMMON VARIANTS

KW - ANGIOTENSINOGEN

KW - METAANALYSIS

KW - POPULATION

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

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

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this