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Genome-wide association study identifies eight loci associated with blood pressure.

ABSTRACT: Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ? 71,225 European ancestry, N ? 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

SUBMITTER: Newton-Cheh C

PROVIDER: S-EPMC2891673 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Genome-wide association study identifies eight loci associated with blood pressure.

Newton-Cheh Christopher C Johnson Toby T Gateva Vesela V Tobin Martin D MD Bochud Murielle M Coin Lachlan L Najjar Samer S SS Zhao Jing Hua JH Heath Simon C SC Eyheramendy Susana S Papadakis Konstantinos K Voight Benjamin F BF Scott Laura J LJ Zhang Feng F Farrall Martin M Tanaka Toshiko T Wallace Chris C Chambers John C JC Khaw Kay-Tee KT Nilsson Peter P van der Harst Pim P Polidoro Silvia S Grobbee Diederick E DE Onland-Moret N Charlotte NC Bots Michiel L ML Wain Louise V LV Elliott Katherine S KS Teumer Alexander A Luan Jian'an J Lucas Gavin G Kuusisto Johanna J Burton Paul R PR Hadley David D McArdle Wendy L WL Brown Morris M Dominiczak Anna A Newhouse Stephen J SJ Samani Nilesh J NJ Webster John J Zeggini Eleftheria E Beckmann Jacques S JS Bergmann Sven S Lim Noha N Song Kijoung K Vollenweider Peter P Waeber Gerard G Waterworth Dawn M DM Yuan Xin X Groop Leif L Orho-Melander Marju M Allione Alessandra A Di Gregorio Alessandra A Guarrera Simonetta S Panico Salvatore S Ricceri Fulvio F Romanazzi Valeria V Sacerdote Carlotta C Vineis Paolo P Barroso Inês I Sandhu Manjinder S MS Luben Robert N RN Crawford Gabriel J GJ Jousilahti Pekka P Perola Markus M Boehnke Michael M Bonnycastle Lori L LL Collins Francis S FS Jackson Anne U AU Mohlke Karen L KL Stringham Heather M HM Valle Timo T TT Willer Cristen J CJ Bergman Richard N RN Morken Mario A MA Döring Angela A Gieger Christian C Illig Thomas T Meitinger Thomas T Org Elin E Org Elin E Pfeufer Arne A Wichmann H Erich HE Kathiresan Sekar S Marrugat Jaume J O'Donnell Christopher J CJ Schwartz Stephen M SM Siscovick David S DS Subirana Isaac I Freimer Nelson B NB Hartikainen Anna-Liisa AL McCarthy Mark I MI O'Reilly Paul F PF Peltonen Leena L Pouta Anneli A de Jong Paul E PE Snieder Harold H van Gilst Wiek H WH Clarke Robert R Goel Anuj A Hamsten Anders A Peden John F JF Seedorf Udo U Syvänen Ann-Christine AC Tognoni Giovanni G Lakatta Edward G EG Sanna Serena S Scheet Paul P Schlessinger David D Scuteri Angelo A Dörr Marcus M Ernst Florian F Felix Stephan B SB Homuth Georg G Lorbeer Roberto R Reffelmann Thorsten T Rettig Rainer R Völker Uwe U Galan Pilar P Gut Ivo G IG Hercberg Serge S Lathrop G Mark GM Zelenika Diana D Deloukas Panos P Soranzo Nicole N Williams Frances M FM Zhai Guangju G Salomaa Veikko V Laakso Markku M Elosua Roberto R Forouhi Nita G NG Völzke Henry H Uiterwaal Cuno S CS van der Schouw Yvonne T YT Numans Mattijs E ME Matullo Giuseppe G Navis Gerjan G Berglund Göran G Bingham Sheila A SA Kooner Jaspal S JS Connell John M JM Bandinelli Stefania S Ferrucci Luigi L Watkins Hugh H Spector Tim D TD Tuomilehto Jaakko J Altshuler David D Strachan David P DP Laan Maris M Meneton Pierre P Wareham Nicholas J NJ Uda Manuela M Jarvelin Marjo-Riitta MR Mooser Vincent V Melander Olle O Loos Ruth J F RJ Elliott Paul P Abecasis Gonçalo R GR Caulfield Mark M Munroe Patricia B PB

Nature genetics 20090510 6

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico ...[more]

PMID: 19430483

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Project description:BackgroundHypertension is a crucial risk factor for developing cardiovascular disease and reducing life expectancy. We aimed to detect DNA methylation (DNAm) variants potentially related to systolic blood pressure (SBP) and diastolic blood pressure (DBP) by conducting epigenome-wide association studies in 60 and 59 Chinese monozygotic twin pairs, respectively.MethodsGenome-wide DNA methylation profiling in whole blood of twins was performed using Reduced Representation Bisulfite Sequencing, yielding 551,447 raw CpGs. Association between DNAm of single CpG and blood pressure was tested by applying generalized estimation equation. Differentially methylated regions (DMRs) were identified by comb-P approach. Inference about Causation through Examination of Familial Confounding was utilized to perform the causal inference. Ontology enrichment analysis was performed using Genomic Regions Enrichment of Annotations Tool. Candidate CpGs were quantified using Sequenom MassARRAY platform in a community population. Weighted gene co-expression network analysis (WGCNA) was conducted using gene expression data.ResultsThe median age of twins was 52 years (95% range 40, 66). For SBP, 31 top CpGs (p < 1 × 10-4) and 8 DMRs were identified, with several DMRs within NFATC1, CADM2, IRX1, COL5A1, and LRAT. For DBP, 43 top CpGs (p < 1 × 10-4) and 12 DMRs were identified, with several DMRs within WNT3A, CNOT10, and DAB2IP. Important pathways, such as Notch signaling pathway, p53 pathway by glucose deprivation, and Wnt signaling pathway, were significantly enriched for SBP and DBP. Causal inference analysis suggested that DNAm at top CpGs within NDE1, MYH11, SRRM1P2, and SMPD4 influenced SBP, while SBP influenced DNAm at CpGs within TNK2. DNAm at top CpGs within WNT3A influenced DBP, while DBP influenced DNAm at CpGs within GNA14. Three CpGs mapped to WNT3A and one CpG mapped to COL5A1 were validated in a community population, with a hypermethylated and hypomethylated direction in hypertension cases, respectively. Gene expression analysis by WGCNA further identified some common genes and enrichment terms.ConclusionWe detect many DNAm variants that may be associated with blood pressure in whole blood, particularly the loci within WNT3A and COL5A1. Our findings provide new clues to the epigenetic modification underlying hypertension pathogenesis.

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Genome-wide association study identifies eight loci associated with blood pressure.

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Genome-wide association study identifies eight loci associated with blood pressure.

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