DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.

TitleDNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.
Publication TypeJournal Article
Year of Publication2017
AuthorsRichard, MA, Huan, T, Ligthart, S, Gondalia, R, Jhun, MA, Brody, JA, Irvin, MR, Marioni, R, Shen, J, Tsai, P-C, Montasser, ME, Jia, Y, Syme, C, Salfati, EL, Boerwinkle, E, Guan, W, Mosley, TH, Bressler, J, Morrison, AC, Liu, C, Mendelson, MM, Uitterlinden, AG, van Meurs, JB, Franco, OH, Zhang, G, Li, Y, Stewart, JD, Bis, JC, Psaty, BM, Chen, Y-DIda, Kardia, SLR, Zhao, W, Turner, ST, Absher, D, Aslibekyan, S, Starr, JM, McRae, AF, Hou, L, Just, AC, Schwartz, JD, Vokonas, PS, Menni, C, Spector, TD, Shuldiner, A, Damcott, CM, Rotter, JI, Palmas, W, Liu, Y, Paus, T, Horvath, S, O'Connell, JR, Guo, X, Pausova, Z, Assimes, TL, Sotoodehnia, N, Smith, JA, Arnett, DK, Deary, IJ, Baccarelli, AA, Bell, JT, Whitsel, E, Dehghan, A, Levy, D, Fornage, M
Corporate AuthorsBIOS Consortium
JournalAm J Hum Genet
Volume101
Issue6
Pagination888-902
Date Published2017 Dec 07
ISSN1537-6605
KeywordsAged, Blood Pressure, CpG Islands, Cross-Sectional Studies, DNA Methylation, Epigenesis, Genetic, Genetic Variation, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Middle Aged, Nerve Tissue Proteins, Quantitative Trait Loci, Tetraspanins
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.

DOI10.1016/j.ajhg.2017.09.028
Alternate JournalAm. J. Hum. Genet.
PubMed ID29198723
PubMed Central IDPMC5812919
Grant ListU01 HL130114 / HL / NHLBI NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
T32 HL098049 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
R01 HL133221 / HL / NHLBI NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
K99 HL136875 / HL / NHLBI NIH HHS / United States