DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

Research output: Contribution to journalArticle

Authors

  • BIOS consortium

External Institution(s)

  • University of Texas Health Science Center at Houston
  • National Institutes of Health
  • Erasmus University Rotterdam
  • University of North Carolina at Chapel Hill
  • University of Michigan, Ann Arbor
  • University of Washington
  • University of Edinburgh
  • University of Queensland
  • University of Utah
  • King's College London
  • University of California at Los Angeles
  • University of Toronto
  • Stanford University
  • Baylor College of Medicine
  • University of Minnesota Twin Cities
  • University of Mississippi
  • Boston University
  • Harvard University
  • Kaiser Permanente
  • Mayo Clinic Rochester, MN
  • HudsonAlpha Institute for Biotechnology
  • University of Alabama at Birmingham
  • Northwestern University
  • Icahn School of Medicine at Mount Sinai
  • University of Maryland, Baltimore
  • Regeneron Pharmaceuticals, Inc.
  • Columbia University
  • Wake Forest University
  • Child Mind Institute, Inc.
  • University of Kentucky
  • Imperial College London

Details

Original languageEnglish (US)
Pages (from-to)888-902
Number of pages15
JournalAmerican journal of human genetics
Volume101
Issue number6
StatusPublished - Dec 7 2017
Peer-reviewedYes

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 < 1.0 × 10−7; replication: N = 7,182, p < 1.6 × 10−3). The replicated methylation sites are heritable (h2 > 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.

    Research areas

  • DNA methylation, Mendelian randomization, blood pressure, epigenome-wide association study, gene expression, sequence variation

Citation formats

APA

BIOS consortium (2017). DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation. American journal of human genetics, 101(6), 888-902. https://doi.org/10.1016/j.ajhg.2017.09.028

Harvard

BIOS consortium 2017, 'DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation', American journal of human genetics, vol. 101, no. 6, pp. 888-902. https://doi.org/10.1016/j.ajhg.2017.09.028