scholarly journals Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group

2018 ◽  
Author(s):  
Tianye Jia ◽  
Congying Chu ◽  
Yun Liu ◽  
Jenny van Dongen ◽  
Nicola J Armstrong ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cell ◽  
Nucleus Accumbens ◽  
Cell Fate ◽  
Large Scale ◽  
Biomarker Discovery ◽  
Association Studies ◽  
Regulatory Elements ◽  
Hippocampal Volume ◽  
Small Sample

ABSTRACTDNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3,337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc) –three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. CpG sites associated with hippocampus volume were significantly enriched within cancer-related genes and within regulatory elements containing the transcriptionally repressive histone H3K27 tri-methylation mark that is vital for stem cell fate specification. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

scholarly journals Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group

2019 ◽  
Author(s):  
Tianye Jia ◽  
Congying Chu ◽  
Yun Liu ◽  
Jenny van Dongen ◽  
Evangelos Papastergios ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Nucleus Accumbens ◽  
Large Scale ◽  
Biomarker Discovery ◽  
Association Studies ◽  
Meta Analysis ◽  
Hippocampal Volume ◽  
Small Sample ◽  
Small Sample Sizes ◽  
Meta Analyses

AbstractDNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)—three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

scholarly journals DNA Methylation and Regulatory Elements during Chicken Germline Stem Cell Differentiation

2018 ◽  
Vol 10 (6) ◽  
pp. 1793-1806 ◽  
Author(s):  
Yanghua He ◽  
Qisheng Zuo ◽  
John Edwards ◽  
Keji Zhao ◽  
Jinzhi Lei ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Stem Cell Differentiation ◽  
Regulatory Elements ◽  
Germline Stem Cell

scholarly journals Dissociable influences of APOE ε4 and polygenic risk of AD dementia on amyloid and cognition

Neurology ◽  
2018 ◽  
Vol 90 (18) ◽  
pp. e1605-e1612 ◽  
Author(s):  
Tian Ge ◽  
Mert R. Sabuncu ◽  
Jordan W. Smoller ◽  
Reisa A. Sperling ◽  
Elizabeth C. Mormino ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Genetic Risk ◽  
Large Scale ◽  
Association Studies ◽  
Specific Effect ◽  
Hippocampal Volume ◽  
Risk Scores ◽  
Hippocampal Atrophy ◽  
Genome Wide Association Studies ◽  
Polygenic Risk

ObjectiveTo investigate the effects of genetic risk of Alzheimer disease (AD) dementia in the context of β-amyloid (Aβ) accumulation.MethodsWe analyzed data from 702 participants (221 clinically normal, 367 with mild cognitive impairment, and 114 with AD dementia) with genetic data and florbetapir PET available. A subset of 669 participants additionally had longitudinal MRI scans to assess hippocampal volume. Polygenic risk scores (PRSs) were estimated with summary statistics from previous large-scale genome-wide association studies of AD dementia. We examined relationships between APOE ε4 status and PRS with longitudinal Aβ and cognitive and hippocampal volume measurements.ResultsAPOE ε4 was strongly related to baseline Aβ, whereas only weak associations between PRS and baseline Aβ were present. APOE ε4 was additionally related to greater memory decline and hippocampal atrophy in Aβ+ participants. When APOE ε4 was controlled for, PRS was related to cognitive decline in Aβ+ participants. Finally, PRSs were associated with hippocampal atrophy in Aβ− participants and weakly associated with baseline hippocampal volume in Aβ+ participants.ConclusionsGenetic risk factors of AD dementia demonstrate effects related to Aβ, as well as synergistic interactions with Aβ. The specific effect of faster cognitive decline in Aβ+ individuals with higher genetic risk may explain the large degree of heterogeneity in cognitive trajectories among Aβ+ individuals. Consideration of genetic variants in conjunction with baseline Aβ may improve enrichment strategies for clinical trials targeting Aβ+ individuals most at risk for imminent cognitive decline.

scholarly journals Leveraging brain cortex-derived molecular data to elucidate epigenetic and transcriptomic drivers of neurological function and disease

2018 ◽  
Author(s):  
Charlie Hatcher ◽  
Caroline L. Relton ◽  
Tom R. Gaunt ◽  
Tom G. Richardson
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Histone Acetylation ◽  
Genetic Variants ◽  
Large Scale ◽  
Genetic Variant ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Epigenetic Mechanisms ◽  
Trait Variation

AbstractIntegrative approaches which harness large-scale molecular datasets can help develop mechanistic insight into findings from genome-wide association studies (GWAS). We have performed extensive analyses to uncover transcriptional and epigenetic processes which may play a role in neurological trait variation.This was undertaken by applying Bayesian multiple-trait colocalization systematically across the genome to identify genetic variants responsible for influencing intermediate molecular phenotypes as well as neurological traits. In this analysis we leveraged high dimensional quantitative trait loci data derived from prefrontal cortex tissue (concerning gene expression, DNA methylation and histone acetylation) and GWAS findings for 5 neurological traits (Neuroticism, Schizophrenia, Educational Attainment, Insomnia and Alzheimer’s disease).There was evidence of colocalization for 118 associations suggesting that the same underlying genetic variant influenced both nearby gene expression as well as neurological trait variation. Of these, 73 associations provided evidence that the genetic variant also influenced proximal DNA methylation and/or histone acetylation. These findings support previous evidence at loci where epigenetic mechanisms may putatively mediate effects of genetic variants on traits, such as KLC1 and schizophrenia. We also uncovered evidence implicating novel loci in neurological disease susceptibility, including genes expressed predominantly in brain tissue such as MDGA1, KIRREL3 and SLC12A5.An inverse relationship between DNA methylation and gene expression was observed more than can be accounted for by chance, supporting previous findings implicating DNA methylation as a transcriptional repressor. Our study should prove valuable in helping future studies prioritise candidate genes and epigenetic mechanisms for in-depth functional follow-up analyses.

scholarly journals Large-scale integration of DNA methylation and gene expression array platforms

2021 ◽  
Author(s):  
Eva E Lancaster ◽  
Vladimir I Vladimirov ◽  
Brien P Riley ◽  
Joseph W Landry ◽  
Roxann Roberson-Nay ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Large Scale ◽  
Association Studies ◽  
Adolescent And Young Adult ◽  
Expression Array ◽  
Cpg Sites ◽  
Disease States ◽  
Large Scale Integration ◽  
Scale Integration

Epigenome-wide association studies (EWAS) aim to provide evidence that marks of DNA methylation (DNAm) have downstream consequences that can result in the development of human diseases. Although these methods have been successful in identifying DNAm patterns associated with disease states, any further characterization of etiologic mechanisms remains elusive. This knowledge gap does not originate from a lack of DNAm-trait associations, but rather stems from study design issues that affect the interpretability of EWAS results. Despite known limitations in predicting the function of a particular CpG site, most EWAS maintain the broad assumption that altered DNAm results in a concomitant change of transcription at the most proximal gene. This study integrated DNAm and gene expression (GE) measurements in two cohorts, the Adolescent and Young Adult Twin Study (AYATS) and the Pregnancy, Race, Environment, Genes (PREG) study, to improve the understanding of epigenomic regulatory mechanisms. CpG sites associated with GE in cis were enriched in areas of transcription factor binding and areas of intermediate-to-low CpG density. CpG sites associated with trans GE were also enriched in areas of known regulatory significance, including enhancer regions. These results highlight issues with restricting DNAm-transcript annotations to small genomic intervals and question the validity of assuming a canonical cis DNAm-GE pathway. Based on these findings, the interpretation of EWAS results is limited in studies without multi-omic support and further research should identify genomic regions in which GE-associated DNAm is overrepresented.

scholarly journals Integration of methylation QTL and enhancer–target gene maps with schizophrenia GWAS summary results identifies novel genes

2019 ◽  
Vol 35 (19) ◽  
pp. 3576-3583 ◽  
Author(s):  
Chong Wu ◽  
Wei Pan
Keyword(s):  
Quantitative Trait ◽  
Large Scale ◽  
Target Gene ◽  
Association Studies ◽  
Regulatory Elements ◽  
Supplementary Information ◽  
Genome Wide Association Studies ◽  
Novel Genes ◽  
Gene Pairs ◽  
Genome Wide

Abstract Motivation Most trait-associated genetic variants identified in genome-wide association studies (GWASs) are located in non-coding regions of the genome and thought to act through their regulatory roles. Results To account for enriched association signals in DNA regulatory elements, we propose a novel and general gene-based association testing strategy that integrates enhancer-target gene pairs and methylation quantitative trait locus data with GWAS summary results; it aims to both boost statistical power for new discoveries and enhance mechanistic interpretability of any new discovery. By reanalyzing two large-scale schizophrenia GWAS summary datasets, we demonstrate that the proposed method could identify some significant and novel genes (containing no genome-wide significant SNPs nearby) that would have been missed by other competing approaches, including the standard and some integrative gene-based association methods, such as one incorporating enhancer-target gene pairs and one integrating expression quantitative trait loci. Availability and implementation Software: wuchong.org/egmethyl.html Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Replication and expansion of epigenome-wide association literature in a black South African population

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
H. Toinét Cronjé ◽  
Hannah R. Elliott ◽  
Cornelie Nienaber-Rousseau ◽  
Marlien Pieters
Keyword(s):  
Dna Methylation ◽  
Alcohol Consumption ◽  
South African ◽  
Large Scale ◽  
Association Studies ◽  
African Population ◽  
450K Array ◽  
Related Factors ◽  
Successful Replication ◽  
Novel Associations

Abstract Background DNA methylation is associated with non-communicable diseases (NCDs) and related traits. Methylation data on continental African ancestries are currently scarce, even though there are known genetic and epigenetic differences between ancestral groups and a high burden of NCDs in Africans. Furthermore, the degree to which current literature can be extrapolated to the understudied African populations, who have limited resources to conduct independent large-scale analysis, is not yet known. To this end, this study examines the reproducibility of previously published epigenome-wide association studies of DNA methylation conducted in different ethinicities, on factors related to NCDs, by replicating findings in 120 South African Batswana men aged 45 to 88 years. In addition, novel associations between methylation and NCD-related factors are investigated using the Illumina EPIC BeadChip. Results Up to 86% of previously identified epigenome-wide associations with NCD-related traits (alcohol consumption, smoking, body mass index, waist circumference, C-reactive protein, blood lipids and age) overlapped with those observed here and a further 13% were directionally consistent. Only 1% of the replicated associations presented with effects opposite to findings in other ancestral groups. The majority of these inconcistencies were associated with population-specific genomic variance. In addition, we identified eight new 450K array CpG associations not previously reported in other ancestries, and 11 novel EPIC CpG associations with alcohol consumption. Conclusions The successful replication of existing EWAS findings in this African population demonstrates that blood-based 450K EWAS findings from commonly investigated ancestries can largely be extrapolated to ethnicities for which epigenetic data are not yet available. Possible population-specific differences in 14% of the tested associations do, however, motivate the need to include a diversity of ethnic groups in future epigenetic research. The novel associations found with the enhanced coverage of the Illumina EPIC array support its usefulness to expand epigenetic literature.

scholarly journals Prenatal smoke effect on mouse offspring Igf1 promoter methylation from fetal stage to adulthood is organ and sex specific

2020 ◽  
Vol 318 (3) ◽  
pp. L549-L561
Author(s):  
Zhijun Zeng ◽  
Karolin F. Meyer ◽  
Khosbayar Lkhagvadorj ◽  
Wierd Kooistra ◽  
Marjan Reinders-Luinge ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Promoter Methylation ◽  
Large Scale ◽  
Developmental Stages ◽  
Association Studies ◽  
Inverse Correlation ◽  
Cpg Sites ◽  
Increased Risk ◽  
Organ Specific ◽  
Health And Disease

Prenatal smoke exposure (PSE) is associated with reduced birth weight, impaired fetal development, and increased risk for diseases later in life. Changes in DNA methylation may be involved, as multiple large-scale epigenome-wide association studies showed that PSE is robustly associated with DNA methylation changes in blood among offspring in early life. Insulin-like growth factor-1 (IGF1) is important in growth, differentiation, and repair processes after injury. However, no studies investigated the organ-specific persistence of PSE-induced methylation change of Igf1 into adulthood. Based on our previous studies on the PSE effect on Igf1 promoter methylation in fetal and neonatal mouse offspring, we now have extended our studies to adulthood. Our data show that basal Igf1 promoter methylation generally increased in the lung but decreased in the liver (except for 2 persistent CpG sites in both organs) across three different developmental stages. PSE changed Igf1 promoter methylation in all three developmental stages, which was organ and sex specific. The PSE effect was less pronounced in adult offspring compared with the fetal and neonatal stages. In addition, the PSE effect in the adult stage was more pronounced in the lung compared with the liver. For most CpG sites, an inverse correlation was found for promoter methylation and mRNA expression when the data of all three stages were combined. This was more prominent in the liver. Our findings provide additional evidence for sex- and organ-dependent prenatal programming, which supports the developmental origins of health and disease (DOHaD) hypothesis.

scholarly journals Epigenetics and Proteomics Join Transcriptomics in the Quest for Tuberculosis Biomarkers

mBio ◽  
2015 ◽  
Vol 6 (5) ◽  
Author(s):  
Maria M. Esterhuyse ◽  
January Weiner ◽  
Etienne Caron ◽  
Andre G. Loxton ◽  
Marco Iannaccone ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Pilot Study ◽  
Large Scale ◽  
Small Sample Size ◽  
Protein Translation ◽  
Small Sample ◽  
Transcriptional Level ◽  
Content Type ◽  
Dna Methylome ◽  
Large Scale Study

ABSTRACT An estimated one-third of the world's population is currently latently infected with Mycobacterium tuberculosis. Latent M. tuberculosis infection (LTBI) progresses into active tuberculosis (TB) disease in ~5 to 10% of infected individuals. Diagnostic and prognostic biomarkers to monitor disease progression are urgently needed to ensure better care for TB patients and to decrease the spread of TB. Biomarker development is primarily based on transcriptomics. Our understanding of biology combined with evolving technical advances in high-throughput techniques led us to investigate the possibility of additional platforms (epigenetics and proteomics) in the quest to (i) understand the biology of the TB host response and (ii) search for multiplatform biosignatures in TB. We engaged in a pilot study to interrogate the DNA methylome, transcriptome, and proteome in selected monocytes and granulocytes from TB patients and healthy LTBI participants. Our study provides first insights into the levels and sources of diversity in the epigenome and proteome among TB patients and LTBI controls, despite limitations due to small sample size. Functionally the differences between the infection phenotypes (LTBI versus active TB) observed in the different platforms were congruent, thereby suggesting regulation of function not only at the transcriptional level but also by DNA methylation and microRNA. Thus, our data argue for the development of a large-scale study of the DNA methylome, with particular attention to study design in accounting for variation based on gender, age, and cell type. IMPORTANCE DNA methylation modifies the transcriptional program of cells. We have focused on two major populations of leukocytes involved in immune response to infectious diseases, granulocytes and monocytes, both of which are professional phagocytes that engulf and kill bacteria. We have interrogated how DNA methylation, gene expression, and protein translation differ in these two cell populations between healthy individuals and patients suffering from TB. To better understand the underlying biologic mechanisms, we harnessed a statistical enrichment analysis, taking advantage of predefined and well-characterized gene sets. Not only were there clear differences on various levels between the two populations, but there were also differences between TB patients and healthy controls in the transcriptome, proteome, and, for the first time, DNA methylome in these cells. Our pilot study emphasizes the value of a large-scale study of the DNA methylome taking into account our findings.

scholarly journals Single cell multi-omics profiling reveals a hierarchical epigenetic landscape during mammalian germ layer specification

2019 ◽  
Author(s):  
Ricard Argelaguet ◽  
Hisham Mohammed ◽  
Stephen J Clark ◽  
L Carine Stapel ◽  
Christel Krueger ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Single Cell ◽  
Cell Fate ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
List Type ◽  
Germ Layer ◽  
Epigenetic Landscape ◽  
Germ Layers ◽  
Cell Fate Decisions

AbstractFormation of the three primary germ layers during gastrulation is an essential step in the establishment of the vertebrate body plan. Recent studies employing single cell RNA-sequencing have identified major transcriptional changes associated with germ layer specification. Global epigenetic reprogramming accompanies these changes, but the role of the epigenome in regulating early cell fate choice remains unresolved, and the coordination between different epigenetic layers is unclear. Here we describe the first single cell triple-omics map of chromatin accessibility, DNA methylation and RNA expression during the exit from pluripotency and the onset of gastrulation in mouse embryos. We find dynamic dependencies between the different molecular layers, with evidence for distinct modes of epigenetic regulation. The initial exit from pluripotency coincides with the establishment of a global repressive epigenetic landscape, followed by the emergence of local lineage-specific epigenetic patterns during gastrulation. Notably, cells committed to mesoderm and endoderm undergo widespread coordinated epigenetic rearrangements, driven by loss of methylation in enhancer marks and a concomitant increase of chromatin accessibility. In striking contrast, the epigenetic landscape of ectodermal cells is already established in the early epiblast. Hence, regulatory elements associated with each germ layer are either epigenetically primed or epigenetically remodelled prior to overt cell fate decisions during gastrulation, providing the molecular logic for a hierarchical emergence of the primary germ layers.HighlightsFirst map of mouse gastrulation using comprehensive single cell triple-omic analysis.Exit from pluripotency is associated with a global repressive epigenetic landscape, driven by a sharp gain of DNA methylation and a gradual decrease of chromatin accessibility.DNA methylation and chromatin accessibility changes in enhancers, but not in promoters, are associated with germ layer formation.Mesoderm and endoderm enhancers become open and demethylated upon lineage commitment.Ectoderm enhancers are primed in the early epiblast and protected from the global repressive dynamics, supporting a default model of ectoderm commitment in vivo.

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