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Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk.

ABSTRACT: Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

SUBMITTER: Warren HR

PROVIDER: S-EPMC5972004 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk.

Warren Helen R HR Evangelou Evangelos E Cabrera Claudia P CP Gao He H Ren Meixia M Mifsud Borbala B Ntalla Ioanna I Surendran Praveen P Liu Chunyu C Cook James P JP Kraja Aldi T AT Drenos Fotios F Loh Marie M Verweij Niek N Marten Jonathan J Karaman Ibrahim I Lepe Marcelo P Segura MP O'Reilly Paul F PF Knight Joanne J Snieder Harold H Kato Norihiro N He Jiang J Tai E Shyong ES Said M Abdullah MA Porteous David D Alver Maris M Poulter Neil N Farrall Martin M Gansevoort Ron T RT Padmanabhan Sandosh S Mägi Reedik R Stanton Alice A Connell John J Bakker Stephan J L SJ Metspalu Andres A Shields Denis C DC Thom Simon S Brown Morris M Sever Peter P Esko Tõnu T Hayward Caroline C van der Harst Pim P Saleheen Danish D Chowdhury Rajiv R Chambers John C JC Chasman Daniel I DI Chakravarti Aravinda A Newton-Cheh Christopher C Lindgren Cecilia M CM Levy Daniel D Kooner Jaspal S JS Keavney Bernard B Tomaszewski Maciej M Samani Nilesh J NJ Howson Joanna M M JM Tobin Martin D MD Munroe Patricia B PB Ehret Georg B GB Wain Louise V LV

Nature genetics 20170130 3

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet ...[more]

PMID: 28135244

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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 analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk.

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Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk.

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