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DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.


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.

SUBMITTER: Richard MA 

PROVIDER: S-EPMC5812919 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.

Richard Melissa A MA   Huan Tianxiao T   Ligthart Symen S   Gondalia Rahul R   Jhun Min A MA   Brody Jennifer A JA   Irvin Marguerite R MR   Marioni Riccardo R   Shen Jincheng J   Tsai Pei-Chien PC   Montasser May E ME   Jia Yucheng Y   Syme Catriona C   Salfati Elias L EL   Boerwinkle Eric E   Guan Weihua W   Mosley Thomas H TH   Bressler Jan J   Morrison Alanna C AC   Liu Chunyu C   Mendelson Michael M MM   Uitterlinden André G AG   van Meurs Joyce B JB   Franco Oscar H OH   Zhang Guosheng G   Li Yun Y   Stewart James D JD   Bis Joshua C JC   Psaty Bruce M BM   Chen Yii-Der Ida YI   Kardia Sharon L R SLR   Zhao Wei W   Turner Stephen T ST   Absher Devin D   Aslibekyan Stella S   Starr John M JM   McRae Allan F AF   Hou Lifang L   Just Allan C AC   Schwartz Joel D JD   Vokonas Pantel S PS   Menni Cristina C   Spector Tim D TD   Shuldiner Alan A   Damcott Coleen M CM   Rotter Jerome I JI   Palmas Walter W   Liu Yongmei Y   Paus Tomáš T   Horvath Steve S   O'Connell Jeffrey R JR   Guo Xiuqing X   Pausova Zdenka Z   Assimes Themistocles L TL   Sotoodehnia Nona N   Smith Jennifer A JA   Arnett Donna K DK   Deary Ian J IJ   Baccarelli Andrea A AA   Bell Jordana T JT   Whitsel Eric E   Dehghan Abbas A   Levy Daniel D   Fornage Myriam M  

American journal of human genetics 20171130 6


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 Inf  ...[more]

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