| Literature DB >> 29198723 |
Melissa A Richard1, Tianxiao Huan2, Symen Ligthart3, Rahul Gondalia4, Min A Jhun5, Jennifer A Brody6, Marguerite R Irvin7, Riccardo Marioni8, Jincheng Shen9, Pei-Chien Tsai10, May E Montasser11, Yucheng Jia12, Catriona Syme13, Elias L Salfati14, Eric Boerwinkle15, Weihua Guan16, Thomas H Mosley17, Jan Bressler18, Alanna C Morrison18, Chunyu Liu19, Michael M Mendelson20, André G Uitterlinden21, Joyce B van Meurs21, Oscar H Franco3, Guosheng Zhang22, Yun Li23, James D Stewart24, Joshua C Bis6, Bruce M Psaty25, Yii-Der Ida Chen12, Sharon L R Kardia5, Wei Zhao5, Stephen T Turner26, Devin Absher27, Stella Aslibekyan7, John M Starr28, Allan F McRae29, Lifang Hou30, Allan C Just31, Joel D Schwartz32, Pantel S Vokonas33, Cristina Menni10, Tim D Spector10, Alan Shuldiner34, Coleen M Damcott11, Jerome I Rotter12, Walter Palmas35, Yongmei Liu36, Tomáš Paus37, Steve Horvath38, Jeffrey R O'Connell11, Xiuqing Guo12, Zdenka Pausova39, Themistocles L Assimes14, Nona Sotoodehnia40, Jennifer A Smith5, Donna K Arnett41, Ian J Deary42, Andrea A Baccarelli32, Jordana T Bell10, Eric Whitsel43, Abbas Dehghan44, Daniel Levy2, Myriam Fornage45.
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.Entities:
Keywords: DNA methylation; Mendelian randomization; blood pressure; epigenome-wide association study; gene expression; sequence variation
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Year: 2017 PMID： 29198723 PMCID： PMC5812919 DOI： 10.1016/j.ajhg.2017.09.028
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025