AN INTEGRATED GENETIC-EPIGENETIC ANALYSIS OF SCHIZOPHRENIA: EVIDENCE FOR CO-LOCALIZATION OF GENETIC ASSOCIATIONS AND DIFFERENTIAL DNA METHYLATION FROM A LARGE META-ANALYSIS OF WHOLE BLOOD DNA

Abstract Highly reproducible smoking-associated DNA methylation changes in whole blood have been reported by many Epigenome-Wide-Association Studies (EWAS). These epigenetic alterations could have important implications for understanding and predicting the risk of smoking-related diseases. To this end, it is important to establish if these DNA methylation changes happen in all blood cell subtypes or if they are cell-type specific. Here, we apply a cell-type deconvolution algorithm to identify cell-type specific DNA methylation signals in seven large EWAS. We find that most of the highly reproducible smoking-associated hypomethylation signatures are more prominent in the myeloid lineage. A meta-analysis further identifies a myeloid-specific smoking-associated hypermethylation signature enriched for DNase Hypersensitive Sites in acute myeloid leukemia. These results may guide the design of future smoking EWAS and have important implications for our understanding of how smoking affects immune-cell subtypes and how this may influence the risk of smoking related diseases.

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Genome-scale sequence data processing and epigenetic analysis of DNA methylation

Hereditas (Beijing) ◽

10.3724/sp.j.1005.2013.00685 ◽

2013 ◽

Vol 35 (6) ◽

pp. 685-694

Author(s):

Ting-Zhang WANG ◽

Gao SHAN ◽

Jian-Hong XU ◽

Qing-Zhong XUE

Keyword(s):

Dna Methylation ◽

Data Processing ◽

Sequence Data ◽

Epigenetic Analysis ◽

Genome Scale ◽

Scale Sequence

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Profile of copper-associated DNA methylation and its association with incident acute coronary syndrome

Clinical Epigenetics ◽

10.1186/s13148-021-01004-w ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Pinpin Long ◽

Qiuhong Wang ◽

Yizhi Zhang ◽

Xiaoyan Zhu ◽

Kuai Yu ◽

...

Keyword(s):

Dna Methylation ◽

Acute Coronary Syndrome ◽

Methylation Level ◽

Meta Analysis ◽

Regulation Of Gene Expression ◽

Density Lipoprotein ◽

Blood Leukocytes ◽

Coronary Syndrome ◽

A Genome ◽

Increased Risk

Abstract Background Acute coronary syndrome (ACS) is a cardiac emergency with high mortality. Exposure to high copper (Cu) concentration has been linked to ACS. However, whether DNA methylation contributes to the association between Cu and ACS is unclear. Methods We measured methylation level at > 485,000 cytosine-phosphoguanine sites (CpGs) of blood leukocytes using Human Methylation 450 Bead Chip and conducted a genome-wide meta-analysis of plasma Cu in a total of 1243 Chinese individuals. For plasma Cu-related CpGs, we evaluated their associations with the expression of nearby genes as well as major cardiovascular risk factors. Furthermore, we examined their longitudinal associations with incident ACS in the nested case-control study. Results We identified four novel Cu-associated CpGs (cg20995564, cg18608055, cg26470501 and cg05825244) within a 5% false discovery rate (FDR). DNA methylation level of cg18608055, cg26470501, and cg05825244 also showed significant correlations with expressions of SBNO2, BCL3, and EBF4 gene, respectively. Higher DNA methylation level at cg05825244 locus was associated with lower high-density lipoprotein cholesterol level and higher C-reactive protein level. Furthermore, we demonstrated that higher cg05825244 methylation level was associated with increased risk of ACS (odds ratio [OR], 1.23; 95% CI 1.02–1.48; P = 0.03). Conclusions We identified novel DNA methylation alterations associated with plasma Cu in Chinese populations and linked these loci to risk of ACS, providing new insights into the regulation of gene expression by Cu-related DNA methylation and suggesting a role for DNA methylation in the association between copper and ACS.

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DNA methylome signatures of prenatal exposure to synthetic glucocorticoids in hippocampus and peripheral whole blood of female guinea pigs in early life

Translational Psychiatry ◽

10.1038/s41398-020-01186-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Aya Sasaki ◽

Margaret E. Eng ◽

Abigail H. Lee ◽

Alisa Kostaki ◽

Stephen G. Matthews

Keyword(s):

Dna Methylation ◽

Whole Blood ◽

Guinea Pigs ◽

Critical Role ◽

Methylation Status ◽

Peripheral Tissues ◽

Epigenetic Biomarkers ◽

Differentially Methylated Genes ◽

Increased Risk ◽

Synthetic Glucocorticoids

AbstractSynthetic glucocorticoids (sGC) are administered to women at risk of preterm delivery, approximately 10% of all pregnancies. In animal models, offspring exposed to elevated glucocorticoids, either by administration of sGC or endogenous glucocorticoids as a result of maternal stress, show increased risk of developing behavioral, endocrine, and metabolic dysregulation. DNA methylation may play a critical role in long-lasting programming of gene regulation underlying these phenotypes. However, peripheral tissues such as blood are often the only accessible source of DNA for epigenetic analyses in humans. Here, we examined the hypothesis that prenatal sGC administration alters DNA methylation signatures in guinea pig offspring hippocampus and whole blood. We compared these signatures across the two tissue types to assess epigenetic biomarkers of common molecular pathways affected by sGC exposure. Guinea pigs were treated with sGC or saline in late gestation. Genome-wide modifications of DNA methylation were analyzed at single nucleotide resolution using reduced representation bisulfite sequencing in juvenile female offspring. Results indicate that there are tissue-specific as well as common methylation signatures of prenatal sGC exposure. Over 90% of the common methylation signatures associated with sGC exposure showed the same directionality of change in methylation. Among differentially methylated genes, 134 were modified in both hippocampus and blood, of which 61 showed methylation changes at identical CpG sites. Gene pathway analyses indicated that prenatal sGC exposure alters the methylation status of gene clusters involved in brain development. These data indicate concordance across tissues of epigenetic programming in response to alterations in glucocorticoid signaling.

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Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases

Clinical Epigenetics ◽

10.1186/s13148-021-01041-5 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Chen Yao ◽

Roby Joehanes ◽

Rory Wilson ◽

Toshiko Tanaka ◽

Luigi Ferrucci ◽

...

Keyword(s):

Gene Expression ◽

Lung Cancer ◽

Dna Methylation ◽

Cigarette Smoking ◽

Association Study ◽

Whole Blood ◽

Lung Diseases ◽

Epigenetic Modification ◽

Blood Gene Expression ◽

Increased Risk

Abstract Background DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases. Results We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data. Conclusions Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.

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Salivary DNA Methylation as an Epigenetic Biomarker for Head and Neck Cancer. Part I: A Diagnostic Accuracy Meta-Analysis

Journal of Personalized Medicine ◽

10.3390/jpm11060568 ◽

2021 ◽

Vol 11 (6) ◽

pp. 568

Author(s):

Óscar Rapado-González ◽

Cristina Martínez-Reglero ◽

Ángel Salgado-Barreira ◽

Laura Muinelo-Romay ◽

Juan Muinelo-Lorenzo ◽

...

Keyword(s):

Dna Methylation ◽

Head And Neck Cancer ◽

Diagnostic Accuracy ◽

Head And Neck ◽

Likelihood Ratio ◽

Neck Cancer ◽

Meta Analysis ◽

Positive Likelihood Ratio ◽

Epigenetic Mechanism ◽

Cochrane Library

DNA hypermethylation is an important epigenetic mechanism for gene expression inactivation in head and neck cancer (HNC). Saliva has emerged as a novel liquid biopsy representing a potential source of biomarkers. We performed a comprehensive meta-analysis to evaluate the overall diagnostic accuracy of salivary DNA methylation for detecting HNC. PubMed EMBASE, Web of Science, LILACS, and the Cochrane Library were searched. Study quality was assessed by the Quality Assessment for Studies of Diagnostic Accuracy-2, and sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (dOR), and their corresponding 95% confidence intervals (CIs) were calculated using a bivariate random-effect meta-analysis model. Meta-regression and subgroup analyses were performed to assess heterogeneity. Eighty-four study units from 18 articles with 8368 subjects were included. The pooled sensitivity and specificity of salivary DNA methylation were 0.39 and 0.87, respectively, while PLR and NLR were 3.68 and 0.63, respectively. The overall area under the curve (AUC) was 0.81 and the dOR was 8.34. The combination of methylated genes showed higher diagnostic accuracy (AUC, 0.92 and dOR, 36.97) than individual gene analysis (AUC, 0.77 and dOR, 6.02). These findings provide evidence regarding the potential clinical application of salivary DNA methylation for HNC diagnosis.

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Urate-induced epigenetic modifications in myeloid cells

Arthritis Research & Therapy ◽

10.1186/s13075-021-02580-1 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

M. Badii ◽

O. I. Gaal ◽

M. C. Cleophas ◽

V. Klück ◽

R. Davar ◽

...

Keyword(s):

Dna Methylation ◽

Whole Blood ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Myeloid Cells ◽

Cytokine Signaling ◽

Human Monocytes ◽

Methylation Array ◽

Histone 3 ◽

Msu Crystals

Abstract Objectives Hyperuricemia is a metabolic condition central to gout pathogenesis. Urate exposure primes human monocytes towards a higher capacity to produce and release IL-1β. In this study, we assessed the epigenetic processes associated to urate-mediated hyper-responsiveness. Methods Freshly isolated human peripheral blood mononuclear cells or enriched monocytes were pre-treated with solubilized urate and stimulated with LPS with or without monosodium urate (MSU) crystals. Cytokine production was determined by ELISA. Histone epigenetic marks were assessed by sequencing immunoprecipitated chromatin. Mice were injected intraarticularly with MSU crystals and palmitate after inhibition of uricase and urate administration in the presence or absence of methylthioadenosine. DNA methylation was assessed by methylation array in whole blood of 76 participants with normouricemia or hyperuricemia. Results High concentrations of urate enhanced the inflammatory response in vitro in human cells and in vivo in mice, and broad-spectrum methylation inhibitors reversed this effect. Assessment of histone 3 lysine 4 trimethylation (H3K4me3) and histone 3 lysine 27 acetylation (H3K27ac) revealed differences in urate-primed monocytes compared to controls. Differentially methylated regions (e.g. HLA-G, IFITM3, PRKAB2) were found in people with hyperuricemia compared to normouricemia in genes relevant for inflammatory cytokine signaling. Conclusion Urate alters the epigenetic landscape in selected human monocytes or whole blood of people with hyperuricemia compared to normouricemia. Both histone modifications and DNA methylation show differences depending on urate exposure. Subject to replication and validation, epigenetic changes in myeloid cells may be a therapeutic target in gout.

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