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New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals

Kraja, Aldi T.; Cook, James P.; Warren, Helen R.; Surendran, Praveen; Liu, Chunyu; Evangelou, Evangelos; Manning, Alisa K.; Grarup, Niels; Drenos, Fotios and Sim, Xueling, et al. (2017) In Circulation: Cardiovascular Genetics 10(5).
Abstract

Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. Methods and Results - Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the... (More)

Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. Methods and Results - Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant. Conclusions - We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

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published
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keywords
blood pressure, exome, genetics, genotype, sample size
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Circulation: Cardiovascular Genetics
volume
10
issue
5
publisher
American Heart Association
external identifiers
  • scopus:85032923056
ISSN
1942-325X
DOI
10.1161/CIRCGENETICS.117.001778
language
English
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yes
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e7eb9d03-e711-4984-b2bb-6aba379dcf96
date added to LUP
2017-12-01 16:01:17
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2018-01-16 11:59:50
@article{e7eb9d03-e711-4984-b2bb-6aba379dcf96,
  abstract     = {<p>Background - Genome-wide association studies have recently identified &gt;400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. Methods and Results - Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P&lt;5×10<sup>-8</sup>) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency &lt;0.01, (rs3025380 at DBH) was genome-wide significant. Conclusions - We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.</p>},
  articleno    = {e001778},
  author       = {Kraja, Aldi T. and Cook, James P. and Warren, Helen R. and Surendran, Praveen and Liu, Chunyu and Evangelou, Evangelos and Manning, Alisa K. and Grarup, Niels and Drenos, Fotios and Sim, Xueling and Smith, Albert Vernon and Amin, Najaf and Blakemore, Alexandra I.F. and Bork-Jensen, Jette and Brandslund, Ivan and Farmaki, Aliki Eleni and Fava, Cristiano and Ferreira, Teresa and Herzig, Karl Heinz and Giri, Ayush and Giulianini, Franco and Grove, Megan L. and Guo, Xiuqing and Harris, Sarah E. and Have, Christian T. and Havulinna, Aki S. and Zhang, He and Jørgensen, Marit E. and Käräjämäki, Anne Mari and Kooperberg, Charles and Linneberg, Allan and Little, Louis and Liu, Yongmei and Bonnycastle, Lori L. and Lu, Yingchang and Mägi, Reedik and Mahajan, Anubha and Malerba, Giovanni and Marioni, Riccardo E. and Mei, Hao and Menni, Cristina and Morrison, Alanna C. and Padmanabhan, Sandosh and Palmas, Walter and Poveda, Alaitz and Rauramaa, Rainer and Rayner, Nigel William and Riaz, Muhammad and Rice, Ken and Richard, Melissa A. and Smith, Jennifer A. and Southam, Lorraine and Stančáková, Alena and Stirrups, Kathleen E. and Tragante, Vinicius and Tuomi, Tiinamaija and Tzoulaki, Ioanna and Varga, Tibor V. and Weiss, Stefan and Yiorkas, Andrianos M. and Young, Robin and Zhang, Weihua and Barnes, Michael R. and Cabrera, Claudia P. and Gao, He and Boehnke, Michael and Boerwinkle, Eric and Chambers, John C. and Connell, John M. and Christensen, Cramer K. and De Boer, Rudolf A. and Deary, Ian J. and Dedoussis, George and Deloukas, Panos and Dominiczak, Anna F. and Dörr, Marcus and Joehanes, Roby and Edwards, Todd L. and Esko, Tõnu and Fornage, Myriam and Franceschini, Nora and Franks, Paul W. and Gambaro, Giovanni and Groop, Leif and Hallmans, Göran and Hansen, Torben and Hayward, Caroline and Heikki, Oksa and Ingelsson, Erik and Tuomilehto, Jaakko and Jarvelin, Marjo Riitta and Kardia, Sharon L.R. and Karpe, Fredrik and Kooner, Jaspal S. and Lakka, Timo A. and Langenberg, Claudia and Lind, Lars and Loos, Ruth J.F. and Laakso, Markku and McCarthy, Mark I. and Melander, Olle and Mohlke, Karen L. and Morris, Andrew P. and Palmer, Colin N.A. and Pedersen, Oluf and Polasek, Ozren and Poulter, Neil R. and Province, Michael A. and Psaty, Bruce M. and Ridker, Paul M. and Rotter, Jerome I. and Rudan, Igor and Salomaa, Veikko and Samani, Nilesh J. and Sever, Peter J. and Skaaby, Tea and Stafford, Jeanette M. and Starr, John M. and Van Der Harst, Pim and Van Der Meer, Peter and Van Duijn, Cornelia M. and Vergnaud, Anne Claire and Gudnason, Vilmundur and Wareham, Nicholas J. and Wilson, James G. and Willer, Cristen J. and Witte, Daniel R. and Zeggini, Eleftheria and Saleheen, Danish and Butterworth, Adam S. and Danesh, John and Asselbergs, Folkert W. and Wain, Louise V. and Ehret, Georg B. and Chasman, Daniel I. and Caulfield, Mark J. and Elliott, Paul and Lindgren, Cecilia M. and Levy, Daniel and Newton-Cheh, Christopher and Munroe, Patricia B. and Howson, Joanna M.M.},
  issn         = {1942-325X},
  keyword      = {blood pressure,exome,genetics,genotype,sample size},
  language     = {eng},
  month        = {10},
  number       = {5},
  publisher    = {American Heart Association},
  series       = {Circulation: Cardiovascular Genetics},
  title        = {New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals},
  url          = {http://dx.doi.org/10.1161/CIRCGENETICS.117.001778},
  volume       = {10},
  year         = {2017},
}