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DNA methylation analysis identifies loci for blood pressure regulation

Research output: Contribution to journalArticle

  • Melissa A Richard
  • Tianxiao Huan
  • Symen Ligthart
  • Rahul Gondalia
  • Min A Jhun
  • Jennifer A Brody
  • Marguerite R Irvin
  • Riccardo Marioni
  • Jincheng Shen
  • Pei-Chien Tsai
  • May E Montasser
  • Yucheng Jia
  • Catriona Syme
  • Elias L Salfati
  • Eric Boerwinkle
  • Weihua Guan
  • Thomas H Mosley
  • Jan Bressler
  • Alanna C Morrison
  • Chunyu Liu
  • Michael M Mendelson
  • André G Uitterlinden
  • Joyce B van Meurs
  • Oscar H Franco
  • Guosheng Zhang
  • Yun Li
  • James D Stewart
  • Joshua C Bis
  • Bruce M Psaty
  • Yii-Der Ida Chen
  • Sharon L R Kardia
  • Wei Zhao
  • Stephen T Turner
  • Devin Absher
  • Stella Aslibekyan
  • John M Starr
  • Allan F McRae
  • Lifang Hou
  • Allan C Just
  • Joel D Schwartz
  • Pantel S Vokonas
  • Cristina Menni
  • Tim D Spector
  • Alan Shuldiner
  • Coleen M Damcott
  • Jerome I Rotter
  • Walter Palmas
  • Yongmei Liu
  • Tomáš Paus
  • Steve Horvath
  • Jeffrey R O'Connell
  • Xiuqing Guo
  • Zdenka Pausova
  • Themistocles L Assimes
  • Nona Sotoodehnia
  • Jennifer A Smith
  • Donna K Arnett
  • Ian J Deary
  • Andrea A Baccarelli
  • Jordana T Bell
  • Eric Whitsel
  • Abbas Dehghan
  • Daniel Levy
  • Myriam Fornage
  • BIOS Consortium

Related Edinburgh Organisations

Original languageEnglish
Pages (from-to)888-902
JournalAmerican Journal of Human Genetics
Volume101
Issue number6
DOIs
StatePublished - 30 Nov 2017

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.

ID: 48292587