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DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

Published on Dec 1, 2017in American Journal of Human Genetics9.92
· DOI :10.1016/j.ajhg.2017.09.028
Melissa Richard8
Estimated H-index: 8
(University of Texas Health Science Center at Houston),
Tianxiao Huan22
Estimated H-index: 22
+ 110 AuthorsMyriam Fornage69
Estimated H-index: 69
(University of Texas Health Science Center at Houston)
Cite
Abstract
Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.
  • References (44)
  • Citations (11)
Cite
References44
Newest
Published on Jun 1, 2017in The FASEB Journal5.39
Jinjing Zhao3
Estimated H-index: 3
(Albany Medical College),
Wen Wu2
Estimated H-index: 2
(Albany Medical College)
+ 8 AuthorsMingfu Wu9
Estimated H-index: 9
(Albany Medical College)
Tetraspanins (TSPANs) comprise a large family of 4-transmembrane domain proteins. The importance of TSPANs in vascular smooth muscle cells (VSMCs) is unexplored. Given that TGF-β1 and myocardin (MYOCD) are potent activators for VSMC differentiation, we screened for TGF-β1 and MYOCD/serum response factor (SRF)–regulated TSPANs in VSMC by using RNA-seq analyses and RNA-arrays. TSPAN2 was found to be the only TSPAN family gene induced by TGF-β1 and MYOCD, and reduced by SRF deficiency in VSMCs. We ...
Published on Mar 1, 2017in Nature Genetics25.45
Helen R. Warren19
Estimated H-index: 19
(QMUL: Queen Mary University of London),
Evangelos Evangelou44
Estimated H-index: 44
(Imperial College London)
+ 56 AuthorsJames P. Cook11
Estimated H-index: 11
(University of Liverpool)
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...
Published on Dec 1, 2016in Genome Biology14.03
Koen F. Dekkers3
Estimated H-index: 3
(LUMC: Leiden University Medical Center),
Maarten van Iterson16
Estimated H-index: 16
(LUMC: Leiden University Medical Center)
+ 31 AuthorsJoris Deelen29
Estimated H-index: 29
(LUMC: Leiden University Medical Center)
Background Cells can be primed by external stimuli to obtain a long-term epigenetic memory. We hypothesize that long-term exposure to elevated blood lipids can prime circulating immune cells through changes in DNA methylation, a process that may contribute to the development of atherosclerosis. To interrogate the causal relationship between triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels and genome-wide DNA methylation while excludin...
Published on Dec 1, 2016in Genome Biology14.03
Tom R. Gaunt46
Estimated H-index: 46
(UoB: University of Bristol),
Hashem A. Shihab13
Estimated H-index: 13
(UoB: University of Bristol)
+ 11 AuthorsKaren M Ho8
Estimated H-index: 8
(UoB: University of Bristol)
Background The influence of genetic variation on complex diseases is potentially mediated through a range of highly dynamic epigenetic processes exhibiting temporal variation during development and later life. Here we present a catalogue of the genetic influences on DNA methylation (methylation quantitative trait loci (mQTL)) at five different life stages in human blood: children at birth, childhood, adolescence and their mothers during pregnancy and middle age.
Published on Nov 1, 2016in Cell Reports7.82
Charles E. Breeze6
Estimated H-index: 6
(UCL: University College London),
Dirk S. Paul19
Estimated H-index: 19
(UCL: University College London)
+ 24 AuthorsMattia Frontini22
Estimated H-index: 22
(University of Cambridge)
Epigenome-wide association studies (EWAS) provide an alternative approach for studying human disease through consideration of non-genetic variants such as altered DNA methylation. To advance the complex interpretation of EWAS, we developed eFORGE (http://eforge.cs.ucl.ac.uk/), a new standalone and web-based tool for the analysis and interpretation of EWAS data. eFORGE determines the cell type-specific regulatory component of a set of EWAS-identified differentially methylated positions. This is a...
Published on Oct 1, 2016in Nature Genetics25.45
George B. Ehret46
Estimated H-index: 46
(University of Geneva),
Teresa Ferreira34
Estimated H-index: 34
(University of Oxford)
+ 309 AuthorsStavroula Kanoni48
Estimated H-index: 48
(QMUL: Queen Mary University of London)
To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endotheli...
Published on Oct 1, 2016in Nature Genetics25.45
Chunyu Liu50
Estimated H-index: 50
(BU: Boston University),
Aldi T. Kraja36
Estimated H-index: 36
(WashU: Washington University in St. Louis)
+ 91 AuthorsStefan Weiss10
Estimated H-index: 10
(University of Greifswald)
Daniel Chasman, Daniel Levy, Christopher Newton-Cheh, Georg Ehret and colleagues perform an association meta-analysis for blood pressure in ∼330,000 individuals and identify 31 new risk loci, implicating biological pathways related to vascular function and cardiometabolic traits. Their findings highlight potential therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.
Published on Oct 1, 2016in Nature Genetics25.45
Praveen Surendran16
Estimated H-index: 16
(University of Cambridge),
Fotios Drenos30
Estimated H-index: 30
(UCL: University College London)
+ 206 AuthorsKate Witkowska8
Estimated H-index: 8
(QMUL: Queen Mary University of London)
High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the geneti ...
Published on Mar 1, 2016in Journal of Clinical Hypertension2.44
Teemu J. Niiranen26
Estimated H-index: 26
(National Institute for Health and Welfare),
Aki S. Havulinna45
Estimated H-index: 45
(National Institute for Health and Welfare)
+ 2 AuthorsAntti Jula66
Estimated H-index: 66
(National Institute for Health and Welfare)
The authors investigated whether a genetic risk score (GRS) constructed of 32 single nucleotide polymorphisms would predict incident hypertension and blood pressure (BP) change over time in a population cohort during an 11-year follow-up (n=5402 at baseline, 3266 at follow-up). In multivariable models, GRS was associated with higher systolic/diastolic BP values at baseline (β±standard error [SE], 1.04±0.14/1.11±0.13 mm Hg; P<.0001 for both) and at reinvestigation (β±SE, 0.84±0.18/0.79±0.16 mm Hg...
Cited By11
Newest
Published in Circulation23.05
Golareh Agha10
Estimated H-index: 10
(Columbia University),
Michael M. Mendelson12
Estimated H-index: 12
(Boston Children's Hospital)
+ -3 AuthorsJan Bressler24
Estimated H-index: 24
(University of Texas Health Science Center at Houston)
Published in Electroanalysis2.69
Carlos H.S. Mendes1
Estimated H-index: 1
(UFRPE: Universidade Federal Rural de Pernambuco),
João Gabriel Soares Montenegro (UFRPE: Universidade Federal Rural de Pernambuco)+ -3 AuthorsSeverino Carlos B. Oliveira4
Estimated H-index: 4
(UFRPE: Universidade Federal Rural de Pernambuco)
Published on May 13, 2019in Hypertension7.02
Nabila Kazmi3
Estimated H-index: 3
(UoB: University of Bristol),
Gemma C. Sharp11
Estimated H-index: 11
(UoB: University of Bristol)
+ 40 AuthorsAndrew J Simpkin10
Estimated H-index: 10
(UoB: University of Bristol)
Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mech...
Published on Jul 25, 2019in Journal of Human Hypertension1.94
Valentina Gonzalez-Jaramillo (University of Bern), Eliana Portilla-Fernandez1
Estimated H-index: 1
(EUR: Erasmus University Rotterdam)
+ 8 AuthorsJana Nano (University of Cambridge)
Epigenetic mechanisms might play a role in the pathophysiology of hypertension, a major risk factor for cardiovascular disease and renal failure. We aimed to systematically review studies investigating the association between epigenetic marks (global, candidate-gene or genome-wide methylation of DNA, and histone modifications) and blood pressure or hypertension. Five bibliographic databases were searched until the 7th of December 2018. Of 2984 identified references, 26 articles based on 25 uniqu...
Published on Jul 18, 2019in bioRxiv
Alba Fernández-Sanlés3
Estimated H-index: 3
,
Sergi Sayols-Baixeras8
Estimated H-index: 8
+ 6 AuthorsRoberto Elosua67
Estimated H-index: 67
Background: DNA methylation is associated with atherosclerosis and cardiovascular risk factors. However, little evidence regarding its association with cardiovascular diseases in large studies is currently available. We aimed to assess the association between DNA methylation and cardiovascular events, and to determine both the predictive capacity of the identified loci and the causality of those associations. Methods: We defined two strategies: epigenome-wide (EWAS) and candidate-gene associatio...
Published on May 7, 2019in Nature Reviews Cardiology17.42
Charlotte Andersson31
Estimated H-index: 31
(BU: Boston University),
Andrew D. Johnson61
Estimated H-index: 61
(BU: Boston University)
+ 1 AuthorsR. S. Vasan20
Estimated H-index: 20
(BU: Boston University)
The Framingham Heart Study (FHS) was established in 1948 to improve understanding of the epidemiology of coronary heart disease (CHD) in the USA. In 1961, seminal work identified major risk factors for CHD (high blood pressure, high cholesterol levels and evidence on the electrocardiogram of left ventricular hypertrophy), which later formed the basis for multivariable 10-year and 30-year risk-prediction algorithms. The FHS cohorts now comprise three generations of participants (n ≈ 15,000) and t...
Published on May 1, 2019in American Journal of Epidemiology4.47
Lewis H. Kuller151
Estimated H-index: 151
(University of Pittsburgh)
Published on Mar 28, 2019in bioRxiv
Paul Yousefi16
Estimated H-index: 16
(UoB: University of Bristol),
Paul Darius Yousefi (UoB: University of Bristol)+ 6 AuthorsMatthew Suderman (UoB: University of Bristol)
Recently, an alcohol predictor was developed using DNA methylation at 144 CpG sites (DNAm-Alc) as a biomarker for improved clinical or epidemiologic assessment of alcohol-related ill health. We validate the performance and characterize the drivers of this DNAm-Alc for the first time in independent populations. In N=1,049 parents from the Avon Longitudinal Study of Parents and Children (ALSPAC) Accessible Resource for Integrated Epigenomic Studies (ARIES) at midlife, we found DNAm-Alc explained 7...
Published on Mar 1, 2019in Current Environmental Health Reports
Maria Grau8
Estimated H-index: 8
(University of Valencia),
Golareh Agha10
Estimated H-index: 10
(Columbia University)
+ 2 AuthorsMaria Tellez-Plaza21
Estimated H-index: 21
(Johns Hopkins University)
Purpose of Review Epigenetic modifications are environmentally responsive and may play a mechanistic role in the development of disease. Mendelian randomization uses genetic variation to assess the causal effect of modifiable exposures on health outcomes. We conducted a systematic review of Mendelian randomization studies evaluating the causal role of DNA methylation (DNAm) changes on the development of health states, emphasizing on studies that formally evaluate exposure-DNAm, in addition to DN...
Published on Jan 1, 2019
Catriona Syme13
Estimated H-index: 13
,
Jean Shin6
Estimated H-index: 6
+ 4 AuthorsZdenka Pausova41
Estimated H-index: 41