DNA methylation analysis identifies loci for blood pressure regulation

Richard, Melissa A., Huan, Tianxiao, Ligthart, Symen, Gondalia, Rahul, Jhun, Min A., Brody, Jennifer A., Irvin, Marguerite R., Marioni, Riccardo, Shen, Jincheng, Tsai, Pei-Chien, Montasser, May E., Jia, Yucheng, Syme, Catriona, Salfati, Elias L., Boerwinkle, Eric, Guan, Weihua, Mosley, Thomas H., Bressler, Jan, Morrison, Alanna C., Liu, Chunyu, Mendelson, Michael M., Uitterlinden, André G., van Meurs, Joyce B., Heijmans, Bastiaan T., ’t Hoen, Peter A.C., van Meurs, Joyce, Isaacs, Aaron, Jansen, Rick, Franke, Lude, Boomsma, Dorret I., Pool, René, van Dongen, Jenny, Hottenga, Jouke J., van Greevenbroek, Marleen M.J., Stehouwer, Coen D.A., van der Kallen, Carla J.H., Schalkwijk, Casper G., Wijmenga, Cisca, Zhernakova, Alexandra, Tigchelaar, Ettje F., Slagboom, P. Eline, Beekman, Marian, Deelen, Joris, van Heemst, Diana, Veldink, Jan H., van den Berg, Leonard H., van Duijn, Cornelia M., Hofman, Albert, Uitterlinden, André G., Jhamai, P. Mila, Verbiest, Michael, Suchiman, H. Eka D., Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Mei, Hailiang, van Iterson, Maarten, van Galen, Michiel, Bot, Jan, van ’t Hof, Peter, Deelen, Patrick, Nooren, Irene, Moed, Matthijs, Vermaat, Martijn, Zhernakova, Dasha V., Luijk, René, Bonder, Marc Jan, van Dijk, Freerk, Arindrarto, Wibowo, Kielbasa, Szymon M., Swertz, Morris A., van Zwet, Erik W., 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, Aslibekyan, Stella, Starr, John M., McRae, Allan F., Hou, Lifang, Just, Allan C., Schwartz, Joel D., Vokonas, Pantel S., Menni, Cristina, Spector, Tim D., Shuldiner, Alan, Damcott, Coleen M., Rotter, Jerome I., Palmas, Walter, Liu, Yongmei, Paus, Tomáš, 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, Dehghan, Abbas, Levy, Daniel and Fornage, Myriam (2017) DNA methylation analysis identifies loci for blood pressure regulation. American Journal of Human Genetics, 101 6: 888-902. doi:10.1016/j.ajhg.2017.09.028


Author Richard, Melissa A.
Huan, Tianxiao
Ligthart, Symen
Gondalia, Rahul
Jhun, Min A.
Brody, Jennifer A.
Irvin, Marguerite R.
Marioni, Riccardo
Shen, Jincheng
Tsai, Pei-Chien
Montasser, May E.
Jia, Yucheng
Syme, Catriona
Salfati, Elias L.
Boerwinkle, Eric
Guan, Weihua
Mosley, Thomas H.
Bressler, Jan
Morrison, Alanna C.
Liu, Chunyu
Mendelson, Michael M.
Uitterlinden, André G.
van Meurs, Joyce B.
Heijmans, Bastiaan T.
’t Hoen, Peter A.C.
van Meurs, Joyce
Isaacs, Aaron
Jansen, Rick
Franke, Lude
Boomsma, Dorret I.
Pool, René
van Dongen, Jenny
Hottenga, Jouke J.
van Greevenbroek, Marleen M.J.
Stehouwer, Coen D.A.
van der Kallen, Carla J.H.
Schalkwijk, Casper G.
Wijmenga, Cisca
Zhernakova, Alexandra
Tigchelaar, Ettje F.
Slagboom, P. Eline
Beekman, Marian
Deelen, Joris
van Heemst, Diana
Veldink, Jan H.
van den Berg, Leonard H.
van Duijn, Cornelia M.
Hofman, Albert
Uitterlinden, André G.
Jhamai, P. Mila
Verbiest, Michael
Suchiman, H. Eka D.
Verkerk, Marijn
van der Breggen, Ruud
van Rooij, Jeroen
Lakenberg, Nico
Mei, Hailiang
van Iterson, Maarten
van Galen, Michiel
Bot, Jan
van ’t Hof, Peter
Deelen, Patrick
Nooren, Irene
Moed, Matthijs
Vermaat, Martijn
Zhernakova, Dasha V.
Luijk, René
Bonder, Marc Jan
van Dijk, Freerk
Arindrarto, Wibowo
Kielbasa, Szymon M.
Swertz, Morris A.
van Zwet, Erik W.
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
Aslibekyan, Stella
Starr, John M.
McRae, Allan F.
Hou, Lifang
Just, Allan C.
Schwartz, Joel D.
Vokonas, Pantel S.
Menni, Cristina
Spector, Tim D.
Shuldiner, Alan
Damcott, Coleen M.
Rotter, Jerome I.
Palmas, Walter
Liu, Yongmei
Paus, Tomáš
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
Dehghan, Abbas
Levy, Daniel
Fornage, Myriam
Title DNA methylation analysis identifies loci for blood pressure regulation
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 1537-6605
0002-9297
Publication date 2017-12-07
Year available 2017
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2017.09.028
Open Access Status Not yet assessed
Volume 101
Issue 6
Start page 888
End page 902
Total pages 15
Place of publication Cambridge, MA., United States
Publisher Cell Press
Language eng
Subject 1311 Genetics
2716 Genetics (clinical)
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; replication: N = 7,182, p < 1.6 × 10). The replicated methylation sites are heritable (h > 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.
Keyword Blood pressure
DNA methylation
Epigenome-wide association study
Gene expression
Mendelian randomization
Sequence variation
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID R01 HL105756
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
Institute for Molecular Bioscience - Publications
 
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Created: Sun, 17 Dec 2017, 01:18:10 EST