scholarly journals Epigenetic DNA methylation changes associated with headache chronification: A retrospective case-control study

Cephalalgia ◽  
2017 ◽  
Vol 38 (2) ◽  
pp. 312-322 ◽  
Author(s):  
Bendik S Winsvold ◽  
Priit Palta ◽  
Else Eising ◽  
Christian M Page ◽  
Arn MJM van den Maagdenberg ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Multiple Testing ◽  
Chronic Headache ◽  
Meta Analysis ◽  
Linear Regression Analysis ◽  
Enrichment Analysis ◽  
Functional Enrichment ◽  
Multiple Testing Correction ◽  
Retrospective Case ◽  
Cpg Sites

Background The biological mechanisms of headache chronification are poorly understood. We aimed to identify changes in DNA methylation associated with the transformation from episodic to chronic headache. Methods Participants were recruited from the population-based Norwegian HUNT Study. Thirty-six female headache patients who transformed from episodic to chronic headache between baseline and follow-up 11 years later were matched against 35 controls with episodic headache. DNA methylation was quantified at 485,000 CpG sites, and changes in methylation level at these sites were compared between cases and controls by linear regression analysis. Data were analyzed in two stages (Stages 1 and 2) and in a combined meta-analysis. Results None of the top 20 CpG sites identified in Stage 1 replicated in Stage 2 after multiple testing correction. In the combined meta-analysis the strongest associated CpG sites were related to SH2D5 and NPTX2, two brain-expressed genes involved in the regulation of synaptic plasticity. Functional enrichment analysis pointed to processes including calcium ion binding and estrogen receptor pathways. Conclusion In this first genome-wide study of DNA methylation in headache chronification several potentially implicated loci and processes were identified. The study exemplifies the use of prospectively collected population cohorts to search for epigenetic mechanisms of disease.

scholarly journals Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

2018 ◽  
Author(s):  
David M. Howard ◽  
Mark J. Adams ◽  
Toni-Kim Clarke ◽  
Jonathan D. Hafferty ◽  
Jude Gibson ◽  
...  
Keyword(s):  
Multiple Testing ◽  
Drug Repositioning ◽  
Association Studies ◽  
Meta Analysis ◽  
Enrichment Analysis ◽  
Brain Regions ◽  
Genome Wide Association Studies ◽  
Multiple Testing Correction ◽  
Synaptic Structure ◽  
Genome Wide

AbstractMajor depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant following multiple testing correction. Based on the putative genes associated with depression this work also highlights several potential drug repositioning opportunities. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.

scholarly journals Smoking, DNA Methylation, and Breast Cancer: A Mendelian Randomization Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Haibo Tang ◽  
Desong Yang ◽  
Chaofei Han ◽  
Ping Mu
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Multiple Testing ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Cancer Tissue ◽  
Nucleotide Polymorphisms ◽  
Multiple Testing Correction ◽  
Cpg Sites ◽  
Meta Analyses

BackgroundSmoking was strongly associated with breast cancer in previous studies. Whether smoking promotes breast cancer through DNA methylation remains unknown.MethodsTwo-sample Mendelian randomization (MR) analyses were conducted to assess the causal effect of smoking-related DNA methylation on breast cancer risk. We used 436 smoking-related CpG sites extracted from 846 middle-aged women in the ARIES project as exposure data. We collected summary data of breast cancer from one of the largest meta-analyses, including 69,501 cases for ER+ breast cancer and 21,468 cases for ER− breast cancer. A total of 485 single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for smoking-related DNA methylation. We further performed an MR Steiger test to estimate the likely direction of causal estimate between DNA methylation and breast cancer. We also conducted colocalization analysis to evaluate whether smoking-related CpG sites shared a common genetic causal SNP with breast cancer in a given region.ResultsWe established four significant associations after multiple testing correction: the CpG sites of cg2583948 [OR = 0.94, 95% CI (0.91–0.97)], cg0760265 [OR = 1.07, 95% CI (1.03–1.11)], cg0420946 [OR = 0.95, 95% CI (0.93–0.98)], and cg2037583 [OR =1.09, 95% CI (1.04–1.15)] were associated with the risk of ER+ breast cancer. All the four smoking-related CpG sites had a larger variance than that in ER+ breast cancer (all p < 1.83 × 10−11) in the MR Steiger test. Further colocalization analysis showed that there was strong evidence (based on PPH4 > 0.8) supporting a common genetic causal SNP between the CpG site of cg2583948 [with IMP3 expression (PPH4 = 0.958)] and ER+ breast cancer. There were no causal associations between smoking-related DNA methylation and ER− breast cancer.ConclusionsThese findings highlight potential targets for the prevention of ER+ breast cancer. Tissue-specific epigenetic data are required to confirm these results.

scholarly journals Epigenome-wide meta-analysis of DNA methylation differences in prefrontal cortex implicates the immune processes in Alzheimer’s disease

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Lanyu Zhang ◽  
Tiago C. Silva ◽  
Juan I. Young ◽  
Lissette Gomez ◽  
Michael A. Schmidt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Prefrontal Cortex ◽  
Biomarker Discovery ◽  
Meta Analysis ◽  
Enrichment Analysis ◽  
Braak Stage ◽  
Polycomb Repressive Complex 2 ◽  
Differentially Methylated Genes

AbstractDNA methylation differences in Alzheimer’s disease (AD) have been reported. Here, we conducted a meta-analysis of more than 1000 prefrontal cortex brain samples to prioritize the most consistent methylation differences in multiple cohorts. Using a uniform analysis pipeline, we identified 3751 CpGs and 119 differentially methylated regions (DMRs) significantly associated with Braak stage. Our analysis identified differentially methylated genes such as MAMSTR, AGAP2, and AZU1. The most significant DMR identified is located on the MAMSTR gene, which encodes a cofactor that stimulates MEF2C. Notably, MEF2C cooperates with another transcription factor, PU.1, a central hub in the AD gene network. Our enrichment analysis highlighted the potential roles of the immune system and polycomb repressive complex 2 in pathological AD. These results may help facilitate future mechanistic and biomarker discovery studies in AD.

scholarly journals Longitudinal Changes of One-Carbon Metabolites and Amino Acid Concentrations during Pregnancy in the Women First Maternal Nutrition Trial

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Stephanie P Gilley ◽  
Nicholas E Weaver ◽  
Evan L Sticca ◽  
Purevsuren Jambal ◽  
Alexandra Palacios ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Amino Acid ◽  
Multiple Testing ◽  
Maternal Nutrition ◽  
Longitudinal Research ◽  
Maternal Blood ◽  
Replication Cohort ◽  
Multiple Testing Correction ◽  
Group A ◽  
Study Sites

ABSTRACT Background Maternal dietary restriction and supplementation of one-carbon (1C) metabolites can impact offspring growth and DNA methylation. However, longitudinal research of 1C metabolite and amino acid (AA) concentrations over the reproductive cycle of human pregnancy is limited. Objective To investigate longitudinal 1C metabolite and AA concentrations prior to and during pregnancy and the effects of a small-quantity lipid-based nutrition supplement (LNS) containing >20 micronutrients and prepregnancy BMI (ppBMI). Methods This study was an ancillary study of the Women First Trial (NCT01883193, clinicaltrials.gov) focused on a subset of Guatemalan women (n = 134), 49% of whom entered pregnancy with a BMI ≥25 kg/m2. Ninety-five women received LNS during pregnancy (+LNS group), while the remainder did not (−LNS group). A subset of women from the Pakistan study site (n = 179) were used as a replication cohort, 124 of whom received LNS. Maternal blood was longitudinally collected on dried blood spot (DBS) cards at preconception, and at 12 and 34 wk gestation. A targeted metabolomics assay was performed on DBS samples at each time point using LC-MS/MS. Longitudinal analyses were performed using linear mixed modeling to investigate the influence of time, LNS, and ppBMI. Results Concentrations of 23 of 27 metabolites, including betaine, choline, and serine, changed from preconception across gestation after application of a Bonferroni multiple testing correction (P < 0.00185). Sixteen of those metabolites showed similar changes in the replication cohort. Asymmetric and symmetric dimethylarginine were decreased by LNS in the participants from Guatemala. Only tyrosine was statistically associated with ppBMI at both study sites. Conclusions Time influenced most 1C metabolite and AA concentrations with a high degree of similarity between the 2 diverse study populations. These patterns were not significantly altered by LNS consumption or ppBMI. Future investigations will focus on 1C metabolite changes associated with infant outcomes, including DNA methylation. This trial was registered at clinicaltrials.gov as NCT01883193.

scholarly journals P13.15 DNA methylation abnormalities in non-promoter regulatory regions are associated with invasive behavior in pituitary tumors

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii65-iii66
Author(s):  
M Q S Mosella ◽  
T S Sabedot ◽  
T M Malta ◽  
J Rock ◽  
M Felicella ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Target Genes ◽  
Meta Analysis ◽  
Differentially Expressed Gene ◽  
Cell Movement ◽  
Pituitary Tumors ◽  
P Value ◽  
Regulatory Regions ◽  
Cpg Sites ◽  
Invasive Behavior

Abstract BACKGROUND Despite histologically benign, pituitary tumors (PT) may invade important adjacent neurovascular structures which can incur in significant comorbidities preventing a complete surgical resection and contributing to resistance to medical treatment. DNA methylation clearly stratified PT based on their functional status i.e. nonfunctioning PTs (NFPTs) from functioning PT (FPTs). However associations of methylation aberrations with invasive behavior is less clear. MATERIAL AND METHODS In order to evaluate whether DNA methylation alterations in regulatory regions other than promoter and coding regions are associated with invasive behavior we performed a meta-analysis of the genome-wide methylome of three public available PT cohorts plus our own (Illumina HumanMethylation platforms- 450K/EPIC). Pituitary specimens comprised of 43 invasive pituitary tumors (InvPT) and 37 noninvasive (NInvPT); 12 FPT and 68 NFPTs, in addition to 20 non-tumor pituitaries. RNA-seq data were available for one cohort (n=23, 12 InvPT,11NInvPT) and integrated with DNA methylation. Invasiveness criteria was based on Knosp grade >= 2 and/or sphenoid or dural invasion. RESULTS Wilcoxon Rank-sum test; Δβ=0.15; p-value <0.001 identified 58 differentially methylated CpG sites in InvPT that were mainly hypomethylated (95%) in relation to NInvPT. NInvPT methylation profile was similar to non-tumor specimens, despite its heterogeneity. Thirty-four percent (n=20) of the differentially methylated CpG sites were located within predicted enhancer regions distributed in intronic (40%), intergenic (40%) and promoter (20%) regions. Predicted enhancer-target genes were enriched for actin filament cell movement, response to starvation, growth factor stimulus and protein autophosporilation pathways. Among them, ZNF625 and INO80E were found mostly negative correlated among methylation and expression data (-0.50 and -0.48, respectively), besides DOC2A found to be one potentially differentially expressed gene under enhancer control (log2FC > 0.2, pvalue <0.05). CONCLUSION Our results suggest that methylation alterations in predicted regulatory regions, such as enhancers, annotated in non-promoter regions (introns and intergenic) may contribute to the invasive behavior of PT.

scholarly journals DNA methylation is associated with lung function in never smokers

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Maaike de Vries ◽  
◽  
Ivana Nedeljkovic ◽  
Diana A. van der Plaat ◽  
Alexandra Zhernakova ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Lung Function ◽  
Ribosome Biogenesis ◽  
Meta Analysis ◽  
Smoking History ◽  
Rotterdam Study ◽  
Main Risk Factor ◽  
Cpg Sites ◽  
Never Smokers ◽  
Integrative Omics

Abstract Background Active smoking is the main risk factor for COPD. Here, epigenetic mechanisms may play a role, since cigarette smoking is associated with differential DNA methylation in whole blood. So far, it is unclear whether epigenetics also play a role in subjects with COPD who never smoked. Therefore, we aimed to identify differential DNA methylation associated with lung function in never smokers. Methods We determined epigenome-wide DNA methylation levels of 396,243 CpG-sites (Illumina 450 K) in blood of never smokers in four independent cohorts, LifeLines COPD&C (N = 903), LifeLines DEEP (N = 166), Rotterdam Study (RS)-III (N = 150) and RS-BIOS (N = 206). We meta-analyzed the cohort-specific methylation results to identify differentially methylated CpG-sites with FEV1/FVC. Expression Quantitative Trait Methylation (eQTM) analysis was performed in the Biobank-based Integrative Omics Studies (BIOS). Results A total of 36 CpG-sites were associated with FEV1/FVC in never smokers at p-value< 0.0001, but the meta-analysis did not reveal any epigenome-wide significant CpG-sites. Of interest, 35 of these 36 CpG-sites have not been associated with lung function before in studies including subjects irrespective of smoking history. Among the top hits were cg10012512, cg02885771, annotated to the gene LTV1 Ribosome Biogenesis factor (LTV1), and cg25105536, annotated to Kelch Like Family Member 32 (KLHL32). Moreover, a total of 11 eQTMS were identified. Conclusions With the identification of 35 CpG-sites that are unique for never smokers, our study shows that DNA methylation is also associated with FEV1/FVC in subjects that never smoked and therefore not merely related to smoking.

Next-generation RNA sequencing reveals transcriptomic changes after brief exposure to preoperative nab-paclitaxel, bevacizumab, and trastuzumab.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10508-10508
Author(s):  
Vinay Varadan ◽  
Sitharthan Kamalakaran ◽  
Angel Janevski ◽  
Nila Banerjee ◽  
Kimberly Lezon-Geyda ◽  
...  
Keyword(s):  
Multiple Testing ◽  
Day Treatment ◽  
Transcriptional Response ◽  
Enrichment Analysis ◽  
Transcript Abundance ◽  
Differentially Expressed ◽  
Read Length ◽  
Breast Cancers ◽  
Rna Seq ◽  
Multiple Testing Correction

10508 Background: Identification of differentially expressed transcripts after brief exposure to preoperative therapy can help determine likely response markers. We quantify and compare differential gene and isoform expression using RNA-seq on patient samples with 10 day exposure to one dose of trastuzumab, bevacizumab or nab-paclitaxel. Methods: We sequenced transcriptomes of 23 pairs of core biopsy RNA from breast cancers pre/post 10 day exposure to therapy. Paired-end sequencing was done on the Illumina GAII platform using amplified total RNA with 74bp read length, yielding data on transcript abundance for a total of 22,160 genes and 34,449 transcripts. Differential expression of transcripts between pre/post samples was estimated assuming Poisson-distributed read-counts, followed by multiple testing correction and enrichment analysis of 185 KEGG pathways. Results: PAM50-based clustering showed individual samples cluster together, demonstrating that tumor subtypes do not change over the 10-day treatment (SABCS 2011). We identified genes that were significantly differentially expressed (p<0.05; FDR<0.1) in at least 60% of samples within each therapy arm: 780 genes in trastuzumab, 302 in bevacizumab, and 176 in nab-paclitaxel. Surprisingly, only THAP11 and TINF2 were common amongst them. THAP11 is involved in stem cell maintenance and TINF2 is important for regulation of telomere length. Immune system and metabolism-related pathways were commonly affected (p<0.05) across all arms. The bevacizumab arm showed significant down-regulation of angiogenesis-associated genes: ESM1 and VEGFR2 in > 80% of samples. The nab-paclitaxel arm exhibited changes in TGF-beta signaling, Nod-like receptor and Wnt signaling. The trastuzumab arm exhibited consistent alteration of ErbB2 and mTOR pathways, with SOX11 and TOP2B downregulated in every sample. Conclusions: This is the first study to compare gene expression with brief exposure across therapies using RNA-seq technology. The unique aspects of transcriptional response to each treatment underscore the need for specific markers of therapeutic response to nab-paclitaxel, bevacizumab and trastuzumab.

scholarly journals Systematic evaluation of the causal relationship between DNA methylation and C-reactive protein

2018 ◽  
Author(s):  
Esther Walton ◽  
Gibran Hemani ◽  
Abbas Dehghan ◽  
Caroline Relton ◽  
George Davey Smith
Keyword(s):  
Dna Methylation ◽  
Multiple Testing ◽  
Causal Effect ◽  
Systematic Evaluation ◽  
Low Grade ◽  
Genetic Associations ◽  
C Reactive Protein ◽  
Individual Level ◽  
Reactive Protein ◽  
Cpg Sites

AbstractElevated C-reactive protein (CRP) levels are an indicator of chronic low-grade inflammation. Epigenetic modifications, including DNA methylation, have been linked to CRP, but systematic investigations into potential underlying causal relationships have not yet been performed.We systematically performed two-sample Mendelian randomization and colocalization analysis between CRP and DNA methylation levels, using GWAS and EWAS summary statistics as well as individual level data available through the ARIES subset of the Avon Longitudinal Study of Parents and Children (ALSPAC; 1,616 participants).We found no convincing examples for a causal association from CRP to DNA methylation. Testing for the reverse (a putative causal effect of DNA methylation on CRP), we found three CpG sites that had shared genetic effects with CRP levels after correcting for multiple testing (cg26470501 (offspring: beta=0.07 [0.03, 0.11]; mothers: beta=0.08 [0.04, 0.13]), cg27023597 (offspring: beta=0.18 [0.10, 0.25]; mothers: beta=0.20 [0.12, 0.28]) and cg12054453 (offspring: beta=0.09 [0.05, 0.13])) influenced CRP levels. For all three CpG sites, linked to the genes TMEM49, BCL3 and MIR21, increased methylation related to an increase in CRP levels. Two CpGs (cg27023597 and cg12054453) were influenced by SNPs in genomic regions that had not previously been implicated in CRP GWASs, implicating them as novel genetic associations.Overall, our findings suggest that CRP associations with DNA methylation are more likely to be driven by either confounding or causal influences of DNA methylation on CRP levels, rather than the reverse.

scholarly journals RNA Sequencing Reveals Key Metabolic Pathways Are Modified by Short-Term Whole Egg Consumption

2021 ◽  
Vol 8 ◽  
Author(s):  
Amanda E. Bries ◽  
Joe L. Webb ◽  
Brooke Vogel ◽  
Claudia Carrillo ◽  
Timothy A. Day ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Multiple Testing ◽  
Cholesterol Biosynthesis ◽  
Principal Component ◽  
Enrichment Analysis ◽  
Dietary Treatment ◽  
Glutathione Metabolism ◽  
Multiple Testing Correction ◽  
Egg Consumption ◽  
Whole Egg

Eggs are protein-rich, nutrient-dense, and contain bioactive ingredients that have been shown to modify gene expression and impact health. To understand the effects of egg consumption on tissue-specific mRNA and microRNA expression, we examined the role of whole egg consumption (20% protein, w/w) on differentially expressed genes (DEGs) between rat (n = 12) transcriptomes in the prefrontal cortex (PFC), liver, kidney, and visceral adipose tissue (VAT). Principal component analysis with hierarchical clustering was used to examine transcriptome profiles between dietary treatment groups. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis as well as genetic network and disease enrichment analysis to examine which metabolic pathways were the most predominantly altered in each tissue. Overall, our data demonstrates that whole egg consumption for 2 weeks modified the expression of 52 genes in the PFC, 22 genes in VAT, and two genes in the liver (adj p &lt; 0.05). Additionally, 16 miRNAs were found to be differentially regulated in the PFC, VAT, and liver, but none survived multiple testing correction. The main pathways influenced by WE consumption were glutathione metabolism in VAT and cholesterol biosynthesis in the PFC. These data highlight key pathways that may be involved in diseases and are impacted by acute consumption of a diet containing whole eggs.

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