Exposure to arsenic at different life-stages and DNA methylation meta-analysis in buccal cells and leukocytes

Abstract Background Arsenic (As) exposure through drinking water is a global public health concern. Epigenetic dysregulation including changes in DNA methylation (DNAm), may be involved in arsenic toxicity. Epigenome-wide association studies (EWAS) of arsenic exposure have been restricted to single populations and comparison across EWAS has been limited by methodological differences. Leveraging data from epidemiological studies conducted in Chile and Bangladesh, we use a harmonized data processing and analysis pipeline and meta-analysis to combine results from four EWAS. Methods DNAm was measured among adults in Chile with and without prenatal and early-life As exposure in PBMCs and buccal cells (N = 40, 850K array) and among men in Bangladesh with high and low As exposure in PBMCs (N = 32, 850K array; N = 48, 450K array). Linear models were used to identify differentially methylated positions (DMPs) and differentially variable positions (DVPs) adjusting for age, smoking, cell type, and sex in the Chile cohort. Probes common across EWAS were meta-analyzed using METAL, and differentially methylated and variable regions (DMRs and DVRs, respectively) were identified using comb-p. KEGG pathway analysis was used to understand biological functions of DMPs and DVPs. Results In a meta-analysis restricted to PBMCs, we identified one DMP and 23 DVPs associated with arsenic exposure; including buccal cells, we identified 3 DMPs and 19 DVPs (FDR < 0.05). Using meta-analyzed results, we identified 11 DMRs and 11 DVRs in PBMC samples, and 16 DMRs and 19 DVRs in PBMC and buccal cell samples. One region annotated to LRRC27 was identified as a DMR and DVR. Arsenic-associated KEGG pathways included lysosome, autophagy, and mTOR signaling, AMPK signaling, and one carbon pool by folate. Conclusions Using a two-step process of (1) harmonized data processing and analysis and (2) meta-analysis, we leverage four DNAm datasets from two continents of individuals exposed to high levels of As prenatally and during adulthood to identify DMPs and DVPs associated with arsenic exposure. Our approach suggests that standardizing analytical pipelines can aid in identifying biological meaningful signals.

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Paternal body mass index and offspring DNA methylation: findings from the PACE consortium

10.1101/2020.03.10.20020099 ◽

2020 ◽

Cited By ~ 1

Author(s):

Gemma C Sharp ◽

Rossella Alfano ◽

Akram Ghantous ◽

Jose Urquiza ◽

Sheryl L Rifas-Shiman ◽

...

Keyword(s):

Body Mass Index ◽

Dna Methylation ◽

Health Outcomes ◽

Candidate Gene ◽

Body Mass ◽

Association Studies ◽

Meta Analysis ◽

450K Array ◽

Total N ◽

Candidate Gene Studies

AbstractBackgroundAccumulating evidence links paternal adiposity in the peri-conceptional period to offspring health outcomes. DNA methylation has been proposed as a mediating mechanism, but very few studies have explored this possibility in humans.Methods and findingsIn the Pregnancy And Childhood Epigenetics (PACE) consortium, we conducted a meta-analysis of co-ordinated epigenome-wide association studies (EWAS) of paternal prenatal Body Mass Index (BMI) (with and without adjustment for maternal BMI) in relation to DNA methylation in offspring blood at birth (13 datasets; total n= 4,894) and in childhood (six datasets; total n = 1,982). We found little evidence of association at either time point: for all CpGs, the False Discovery Rate-adjusted P-values were >0.05. In sex-stratified analyses, we found just four CpGs where there was robust evidence of association in female offspring. To compare our findings to those of other studies, we conducted a systematic review, which identified seven studies, including five candidate gene studies showing associations between paternal BMI/obesity and offspring or sperm DNA methylation at imprinted regions. However, in our own study, we found very little evidence of enrichment for imprinted genes.ConclusionOur findings do not support the hypothesis that paternal BMI around the time of pregnancy is associated with offspring blood DNA methylation, even at imprinted regions.Author SummaryPrevious small, mostly candidate gene studies have shown associations between paternal pre-pregnancy BMI and offspring blood DNA methylation. However, in our large meta-analysis of co-ordinated EWAS results from a total of 19 datasets across two timepoints, we found little evidence to support these findings, even at imprinted regions. This does not rule out the possibility of a paternal epigenetic effect in different tissues, at regions not covered by the 450k array, via different mechanisms, or in populations with greater extremes of paternal BMI. More research is warranted to help understand the size and nature of contributions of paternal adiposity to offspring epigenetics and health outcomes.

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Pulmonary function and risk of Alzheimer dementia: two-sample Mendelian randomization study

10.1101/2020.07.28.20163352 ◽

2020 ◽

Author(s):

Tom C. Russ ◽

Sarah E. Harris ◽

G. David Batty

Keyword(s):

Pulmonary Function ◽

Causal Effect ◽

Association Studies ◽

Forced Expiratory Volume ◽

Health Concern ◽

Mendelian Randomisation ◽

Genome Wide Association Studies ◽

Global Public Health ◽

Alzheimer Dementia ◽

Dementia Risk

ABSTRACTDementia is a major global public health concern and in addition to recognised risk factors there is emerging evidence that poorer pulmonary function is linked with subsequent dementia risk. However, it is unclear if this observed association is causal or whether it might result from confounding. Therefore, we present the first two-sample Mendelian randomisation study of the association between pulmonary function and Alzheimer dementia using the most recent genome-wide association studies to produce instrumental variables for both. We found no evidence of a causal effect of reduced Forced Expiratory Volume in 1 second (FEV1) or Forced Vital Capacity (FVC) on Alzheimer dementia risk (both P>0.35). However, the FEV1/FVC ratio was associated with Alzheimer dementia risk with, in fact, superior function predicting an increased dementia risk (OR 1.12, 95%CI 1.02-1.23; P=0.016) which may result from survivor bias. While we can conclude that there is no causal link between impaired pulmonary function and Alzheimer dementia, our study sheds less light on potential links with other types of dementia.

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

Molecular Psychiatry ◽

10.1038/s41380-019-0605-z ◽

2019 ◽

Cited By ~ 3

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.

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Association between DNA methylation and ADHD symptoms from birth to school age: a prospective meta-analysis

Translational Psychiatry ◽

10.1038/s41398-020-01058-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Alexander Neumann ◽

Esther Walton ◽

Silvia Alemany ◽

Charlotte Cecil ◽

Juan Ramon González ◽

...

Keyword(s):

Dna Methylation ◽

Neurotransmitter Release ◽

Association Studies ◽

Meta Analysis ◽

School Age ◽

Adhd Symptoms ◽

Future Studies ◽

Hyperactivity Disorder ◽

Causal Pathways ◽

Nominal Significance

AbstractAttention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4–15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7–11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance (p < 0.05) in either of the EWAS were correlated between timepoints (ρ = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms (p < 1 × 10–7), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p < 1 × 10−7. In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.

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

Clinical Epigenetics ◽

10.1186/s13148-019-0805-z ◽

2020 ◽

Vol 12 (1) ◽

Cited By ~ 2

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.

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DNA methylation of blood cells is associated with prevalent type 2 diabetes in a meta-analysis of four European cohorts

Clinical Epigenetics ◽

10.1186/s13148-021-01027-3 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Diana L. Juvinao-Quintero ◽

Riccardo E. Marioni ◽

Carolina Ochoa-Rosales ◽

Tom C. Russ ◽

Ian J. Deary ◽

...

Keyword(s):

Risk Factors ◽

Type 2 Diabetes ◽

Dna Methylation ◽

Association Studies ◽

Meta Analysis ◽

Cell Types ◽

Common Risk Factors ◽

Variation Explained

Abstract Background Type 2 diabetes (T2D) is a heterogeneous disease with well-known genetic and environmental risk factors contributing to its prevalence. Epigenetic mechanisms related to changes in DNA methylation (DNAm), may also contribute to T2D risk, but larger studies are required to discover novel markers, and to confirm existing ones. Results We performed a large meta-analysis of individual epigenome-wide association studies (EWAS) of prevalent T2D conducted in four European studies using peripheral blood DNAm. Analysis of differentially methylated regions (DMR) was also undertaken, based on the meta-analysis results. We found three novel CpGs associated with prevalent T2D in Europeans at cg00144180 (HDAC4), cg16765088 (near SYNM) and cg24704287 (near MIR23A) and confirmed three CpGs previously identified (mapping to TXNIP, ABCG1 and CPT1A). We also identified 77 T2D associated DMRs, most of them hypomethylated in T2D cases versus controls. In adjusted regressions among diabetic-free participants in ALSPAC, we found that all six CpGs identified in the meta-EWAS were associated with white cell-types. We estimated that these six CpGs captured 11% of the variation in T2D, which was similar to the variation explained by the model including only the common risk factors of BMI, sex, age and smoking (R2 = 10.6%). Conclusions This study identifies novel loci associated with T2D in Europeans. We also demonstrate associations of the same loci with other traits. Future studies should investigate if our findings are generalizable in non-European populations, and potential roles of these epigenetic markers in T2D etiology or in determining long term consequences of T2D.

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Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus

Nature Communications ◽

10.1038/s41467-021-27198-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Adrienne Tin ◽

Pascal Schlosser ◽

Pamela R. Matias-Garcia ◽

Chris H. L. Thio ◽

Roby Joehanes ◽

...

Keyword(s):

Dna Methylation ◽

Complex Traits ◽

Cardiometabolic Risk ◽

Association Studies ◽

Meta Analysis ◽

Elevated Serum ◽

Complex Trait ◽

Serum Urate ◽

Genome Wide Association Studies ◽

Genome Wide

AbstractElevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E–7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

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DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

10.1101/2020.07.22.215939 ◽

2020 ◽

Author(s):

Jenny van Dongen ◽

Fiona A. Hagenbeek ◽

Matthew Suderman ◽

Peter Roetman ◽

Karen Sugden ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Aggressive Behavior ◽

Peripheral Blood ◽

Association Studies ◽

Meta Analysis ◽

Risk Tolerance ◽

Blood Samples ◽

Chemical Exposures ◽

Starting Point

AbstractDNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N=15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha=1.2×10−7; Bonferroni correction). In cord blood samples of 2,425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r=0.74, p=0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripherl blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range=3-82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

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Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption

10.1101/2020.04.15.042267 ◽

2020 ◽

Author(s):

Irma Karabegović ◽

Eliana Portilla-Fernandez ◽

Yang Li ◽

Jiantao Ma ◽

Silvana C.E. Maas ◽

...

Keyword(s):

Dna Methylation ◽

Observational Studies ◽

Disease Risk ◽

Association Studies ◽

Meta Analysis ◽

Disease Onset ◽

Coffee Consumption ◽

Tea Consumption ◽

Hepatic Lipid Metabolism

AbstractCoffee and tea are extensively consumed beverages worldwide. Observational studies have shown contradictory findings for the association between consumption of these beverages and different health outcomes. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. We conducted epigenome-wide association studies (EWAS) on coffee and tea consumptions in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis revealed 11 CpG sites significantly associated with coffee consumption (P-value <1.1×10-7), nine of them annotated to the genes AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH, and two CpGs suggestively associated with tea consumption (P-value<5.0×10-6). Among these, cg14476101 was significantly associated with expression of its annotated gene PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells showed a correlation with expression levels of lipid-associated genes, suggesting a role of PHGDH in hepatic-lipid metabolism. Collectively, this study indicates that coffee consumption is associated with differential DNA methylation levels at multiple CpGs, and that coffee-associated epigenetic variations may explain the mechanism of action of coffee consumption in conferring disease risk.

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Twin Study of Early-Onset Major Depression Finds DNA Methylation Enrichment for Neurodevelopmental Genes

10.1101/422345 ◽

2018 ◽

Cited By ~ 9

Author(s):

Roxann Roberson-Nay ◽

Aaron R. Wolen ◽

Dana M. Lapato ◽

Eva E. Lancaster ◽

Bradley T. Webb ◽

...

Keyword(s):

Dna Methylation ◽

Major Depression ◽

Early Onset ◽

Time Course ◽

Meta Analysis ◽

Monozygotic Twins ◽

Health Condition ◽

450K Array ◽

Genes And Environment ◽

Genomic Regions

AbstractMajor depression (MD) is a debilitating mental health condition with peak prevalence occurring early in life. Genome-wide examination of DNA methylation (DNAm) offers an attractive comple ment to studies of allelic risk given it can reflect the combined influence of genes and environment. The current study used a co-twin control design to identify differentially and variably methylated regions of the genome that distinguish monozygotic (MZ) twins with and without a lifetime history of early-onset MD. The sample included 150 Caucasian monozygotic twins (73% female;Mage=17.52SD=1.28) assessed during a developmental stage characterized by relatively dis tinct neurophysiological changes. All twins were generally healthy and currently free of medica tions with psychotropic effects. DNAm was measured in peripheral blood cells using the Infinium Human BeadChip 450K Array. MD associations were detected at 760 differentially and variably methylated probes/regions that mapped to 428 genes. Results indicated an association between early-onset MD and many genes and genomic regions involved in neural circuitry formation, pro jection, functioning, and plasticity. Gene enrichment analyses implicated genes related to neuron structures and neurodevelopmental processes including cell-cell adhesion genes (e.g.,CDHs, PCDHAs, PCDHA1C/2C). Genes previously implicated in mood and psychiatric disorders as well as chronic stress (e.g.,HDAC4, NRG1) also were identified. DNAm regions associated with MD where found to overlap genetic loci observed in the latest Psychiatric Genomics Consortium meta‐ analysis of depression. Understanding the time course of epigenetic influences during emerging adulthood may clarify developmental phases where genes modulate individual differences in MD risk.

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