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DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

Citation

Richard, Melissa A.; Huan, Tianxiao; Ligthart, Symen; Gondalia, Rahul; Jhun, Min A.; Brody, Jennifer A.; Irvin, Marguerite Ryan; Marioni, Riccardo E.; Shen, Jincheng; & Tsai, Pei-Chien, et al. (2017). DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation. American Journal of Human Genetics, 101(6), 888-902. PMCID: PMC5812919

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 x 10(-7); replication: N = 7,182, p < 1.6 x 10(-3)). The replicated methylation sites are heritable (h(2) > 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.

URL

http://dx.doi.org/10.1016/j.ajhg.2017.09.028

Reference Type

Journal Article

Year Published

2017

Journal Title

American Journal of Human Genetics

Author(s)

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

PMCID

PMC5812919