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Blood Pressure Loci Identified with a Gene-Centric Array

Johnson, Toby; Gaunt, Tom R.; Newhouse, Stephen J.; Padmanabhan, Sandosh; Tomaszewski, Maciej; Kumari, Meena; Morris, Richard W.; Tzoulaki, Ioanna; O'Brien, Eoin T. and Poulter, Neil R., et al. (2011) In American Journal of Human Genetics 89(6). p.688-700
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... (More)
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. (Less)
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American Journal of Human Genetics
volume
89
issue
6
pages
688 - 700
publisher
Cell Press
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  • wos:000298208700001
  • scopus:83555162484
ISSN
0002-9297
DOI
10.1016/j.ajhg.2011.10.013
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English
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803eaa07-4d42-4102-970a-a6066864541d (old id 2320653)
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2012-02-01 07:35:47
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@article{803eaa07-4d42-4102-970a-a6066864541d,
  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 &lt; 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 &lt; 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.},
  author       = {Johnson, Toby and Gaunt, Tom R. and Newhouse, Stephen J. and Padmanabhan, Sandosh and Tomaszewski, Maciej and Kumari, Meena and Morris, Richard W. and Tzoulaki, Ioanna and O'Brien, Eoin T. and Poulter, Neil R. and Sever, Peter and Shields, Denis C. and Thom, Simon 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 Onipinla, Abiodun and Shaw-Hawkins, Sue and Zhang, Yun 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 Elliott, Paul and Gateva, Vesela and Braund, Peter S. and Burton, Paul R. and Nelson, Christopher P. and Tobin, Martin D. and van der Harst, Pim and Glorioso, Nicola and Neuvrith, Hani and Salvi, Erika and Staessen, Jan A. and Stucchi, Andrea and Devos, Nabila and Jeunemaitre, Xavier and Plouin, Pierre-Francois and Tichet, Jean and Juhanson, Peeter and Org, Elin and Putku, Margus and Sober, Siim and Veldre, Gudrun and Viigimaa, Margus and Levinsson, Anna and Rosengren, Annika and Thelle, Dag S. and Hastie, Claire E. and Hedner, Thomas and Lee, Wai K. and Melander, Olle and Wahlstrand, Bjoern and Hardy, Rebecca and Wong, Andrew and Cooper, Jackie A. and Palmen, Jutta and Chen, Li and Stewart, Alexandre F. R. and Wells, George A. and Westra, Harm-Jan and Wolfs, Marcel G. M. and Clarke, Robert and Franzosi, Maria Grazia and Goel, Anuj and Hamsten, Anders and Lathrop, Mark and Peden, John F. and Seedorf, Udo and Watkins, Hugh and Ouwehand, Willem H. and Sambrook, Jennifer and Stephens, Jonathan and Casas, Juan-Pablo and Drenos, Fotios and Holmes, Michael V. and Kivimaki, Mika and Shah, Sonia and Shah, Tina and Talmud, Philippa J. and Whittaker, John and Wallace, Chris and Delles, Christian and Laan, Mans and Kuh, Diana and Humphries, Steve E. and Nyberg, Fredrik and Cusi, Daniele and Roberts, Robert and Newton-Cheh, Christopher and Franke, Lude and Stanton, Alice V. and Dominiczak, Anna F. and Farrall, Martin and Hingorani, Aroon D. and Samani, Nilesh J. and Caulfield, Mark J. and Munroe, Patricia B.},
  issn         = {0002-9297},
  language     = {eng},
  number       = {6},
  pages        = {688--700},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Blood Pressure Loci Identified with a Gene-Centric Array},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2011.10.013},
  volume       = {89},
  year         = {2011},
}