Dataset Information

Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure.

ABSTRACT: We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with P<1×10^-5. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (P<1×10^-7) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with P<0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 (TXNIP) and cg00716257 (JDP2) determined by environmental effects acting on both systolic BP and methylation levels.

SUBMITTER: Huang Y

PROVIDER: S-EPMC7295009 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure.

Huang Yisong Y Ollikainen Miina M Muniandy Maheswary M Zhang Tao T van Dongen Jenny J Hao Guang G van der Most Peter J PJ Pan Yue Y Pervjakova Natalia N Sun Yan V YV Hui Qin Q Lahti Jari J Fraszczyk Eliza E Lu Xueling X Sun Dianjianyi D Richard Melissa A MA Willemsen Gonneke G Heikkila Kauko K Mateo Leach Irene I Mononen Nina N Kähönen Mika M Hurme Mikko A MA Raitakari Olli T OT Drake Amanda J AJ Perola Markus M Nuotio Marja-Liisa ML Huang Yunfeng Y Khulan Batbayar B Räikkönen Katri K Wolffenbuttel Bruce H R BHR Zhernakova Alexandra A Fu Jingyuan J Zhu Haidong H Dong Yanbin Y van Vliet-Ostaptchouk Jana V JV Franke Lude L Eriksson Johan G JG Fornage Myriam M Milani Lili L Lehtimäki Terho T Vaccarino Viola V Boomsma Dorret I DI van der Harst Pim P de Geus Eco J C EJC Salomaa Veikko V Li Shengxu S Chen Wei W Su Shaoyong S Wilson James J Snieder Harold H Kaprio Jaakko J Wang Xiaoling X

Hypertension (Dallas, Tex. : 1979) 20200610 1

We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with <i>P</i><1×10<sup>-5</sup>. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. ...[more]

PMID: 32520614

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Project description:Hypertension is a crucial risk factor for developing cardiovascular disease and reducing life expectancy. We aimed to detect DNA methylation (DNAm) variants potentially related to systolic blood pressure (SBP) and diastolic blood pressure (DBP) by conducting epigenome-wide association studies in 60 and 59 Chinese monozygotic twin pairs, respectively. Genome-wide DNA methylation profiling in whole blood of twins was performed using Reduced Representation Bisulfite Sequencing, yielding 551,447 raw CpGs. Association between DNAm of single CpG and blood pressure was tested by applying generalized estimation equation. Differentially methylated regions (DMRs) were identified by comb-P approach. Inference about Causation through Examination of Familial Confounding was utilized to perform the causal inference. Ontology enrichment analysis was performed using Genomic Regions Enrichment of Annotations Tool. Candidate CpGs were quantified using Sequenom MassARRAY platform in a community population. Weighted gene co-expression network analysis (WGCNA) was conducted using gene expression data. The median age of twins was 52 years (95% range 40, 66). For SBP, 31 top CpGs (p < 1 × 10-4) and 8 DMRs were identified, with several DMRs within NFATC1, CADM2, IRX1, COL5A1, and LRAT. For DBP, 43 top CpGs (p < 1 × 10-4) and 12 DMRs were identified, with several DMRs within WNT3A, CNOT10, and DAB2IP. Important pathways, such as Notch signaling pathway, p53 pathway by glucose deprivation, and Wnt signaling pathway, were significantly enriched for SBP and DBP. Causal inference analysis suggested that DNAm at top CpGs within NDE1, MYH11, SRRM1P2, and SMPD4 influenced SBP, while SBP influenced DNAm at CpGs within TNK2. DNAm at top CpGs within WNT3A influenced DBP, while DBP influenced DNAm at CpGs within GNA14. Three CpGs mapped to WNT3A and one CpG mapped to COL5A1 were validated in a community population, with a hypermethylated and hypomethylated direction in hypertension cases, respectively. Gene expression analysis by WGCNA further identified some common genes and enrichment terms. We detect many DNAm variants that may be associated with blood pressure in whole blood, particularly the loci within WNT3A and COL5A1. Our findings provide new clues to the epigenetic modification underlying hypertension pathogenesis.

Project description:BackgroundFibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined based on interindividual differences in DNA methylation at cytosine-phosphate-guanine (CpG) sites and vice versa.ObjectivesTo perform an EWAS to examine an association between blood DNA methylation levels and circulating fibrinogen levels to better understand its biological and pathophysiological actions.MethodsWe performed an epigenome-wide association study of circulating fibrinogen levels in 18 037 White, Black, American Indian, and Hispanic participants, representing 14 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Circulating leukocyte DNA methylation was measured using the Illumina 450K array in 12 904 participants and using the EPIC array in 5133 participants. In each study, an epigenome-wide association study of fibrinogen was performed using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without CRP adjustment to examine the role of inflammation.ResultsWe identified 208 and 87 significant CpG sites associated with fibrinogen levels from the 450K (p < 1.03 × 10-7) and EPIC arrays (p < 5.78 × 10-8), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. The examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations of all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant.ConclusionWe identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.

Dataset Information

Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure.

Publications

Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure.

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