scholarly journals DNA methylation in peripheral tissues and Left-handedness

2021 ◽  
Author(s):  
Veronika Odintsova ◽  
Matthew Sudermann ◽  
Fiona Hagenbeek ◽  
Doretta Caramaschi ◽  
Jouke-Jan Hottenga ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Meta Analysis ◽  
Longitudinal Analyses ◽  
Buccal Cells ◽  
Peripheral Tissues ◽  
Cpg Sites ◽  
Left Handedness ◽  
Left Handed ◽  
The Brain ◽  
Correlation Range

Abstract Handedness has low heritability and epigenetic mechanisms have been proposed as an etiological mechanism. To examine this hypothesis, we performed an epigenome-wide association study (EWAS) of left-handedness. In a meta-analysis of 3,914 adults of whole-blood DNA methylation, we observed that CpG sites located in proximity of handedness-associated genetic variants were more strongly associated with left-handedness than other CpG sites (P = 0.04), but did not identify any differentially methylated positions. We identified differentially methylated regions at 20q11.23 (P = 0.00004) and 2p25.1 (P = 0.03), which were less methylated in left-handed adults. In longitudinal analyses of DNA methylation in peripheral blood and buccal cells from children (N = 1,737), we observed moderately stable associations across age (correlation range [0.355–0.578]) but inconsistent across tissues (correlation range [-0.384-0.318]). We conclude that DNA methylation in peripheral tissues captures little of the variance in handedness. Future investigations should consider other more targeted sources of tissue, such as the brain.

scholarly journals The incidence of left-handedness: a meta-analysis [1993]

2019 ◽  
Author(s):  
Ian Christopher McManus
Keyword(s):  
Sex Difference ◽  
Meta Analysis ◽  
Birth Cohorts ◽  
Future Studies ◽  
Left Handedness ◽  
Left Handed ◽  
Method Of Measurement ◽  
Males And Females ◽  
Older Subjects ◽  
Unpublished Manuscripts

A meta-analysis is reported of 88 studies, examining 100 study populations, in which the handedness of 284665 individuals has been assessed. The overall incidence of left-handedness was 7.78%. The incidence of left-handedness was not related to the method of measurement, or the length or number of response items included in inventories. Study populations with lower response rates and smaller study populations showed some evidence of higher incidences of left-handedness, presumably due to response biasses. There was no evidence that the incidence of left-handedness was related to the year of publication of studies; however the incidence of left-handedness was lower in older subjects and in those from earlier birth cohorts, the two effects not being statistically distinguishable.Information was available from 64 study populations concerning the incidence of left-handedness in males and females; overall 8.52% of males were left-handed compared with 6.69% of females, the male incidence being 27.4% higher than that in females. Although there was some suggestion that the sex difference was greater in larger studies, and in studies whose main purpose was not the study of handedness, these differences were not significant. It is concluded that the size of the sex difference is unrelated to any of the moderator variables we have studied.It was not possible to carry out a meta-analysis of degree of handedness due to wide-spread differences in the method of reporting of degree of handedness.We recommend that future studies of handedness should, as a minimum, use one of three standard methods of assessment, so that comparison of studies is facilitated. Note: This manuscript was originally prepared in 1993 but due to problems at a major journal, described briefly, was never eventually published. It has however been cited on a number of occasions, and has been available at https://www.ucl.ac.uk/medical-education/publications/unpublished-manuscripts/meta-analysis-of-handedness . A major meta-analysis of handedness in 2019 by another author has now been submitted which cites this manuscript, and therefore it needs to be available in a more archivable format.

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.

scholarly journals Association between DNA Methylation of the BDNF Promoter Region and Clinical Presentation in Alzheimer's Disease

2015 ◽  
Vol 5 (1) ◽  
pp. 64-73 ◽  
Author(s):  
Tomoyuki Nagata ◽  
Nobuyuki Kobayashi ◽  
Jumpei Ishii ◽  
Shunichiro Shinagawa ◽  
Ritsuko Nakayama ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Methylation Level ◽  
Clinical Presentation ◽  
Neuropsychological Test ◽  
Cpg Sites ◽  
The Brain ◽  
Normal Controls ◽  
Methylation Ratio

Background/Aims: In the present study, we examined whether DNA methylation of the brain-derived neurotrophic factor (BDNF) promoter is associated with the manifestation and clinical presentation of Alzheimer's disease (AD). Methods: Of 20 patients with AD and 20 age-matched normal controls (NCs), the DNA methylation of the BDNF promoter (measured using peripheral blood samples) was completely analyzed in 12 patients with AD and 6 NCs. The resulting methylation levels were compared statistically. Next, we investigated the correlation between the DNA methylation levels and the clinical presentation of AD. Results: The total methylation ratio (in %) of the 20 CpG sites was significantly higher in the AD patients (5.08 ± 5.52%) than in the NCs (2.09 ± 0.81%; p < 0.05). Of the 20 CpG sites, the methylation level at the CpG4 site was significantly higher in the AD subjects than in the NCs (p < 0.05). Moreover, the methylation level was significantly and negatively correlated with some neuropsychological test subscores (registration, recall, and prehension behavior scores; p < 0.05). Conclusion: These results suggest that the DNA methylation of the BDNF promoter may significantly influence the manifestation of AD and might be associated with its neurocognitive presentation.

Integration of public DNA methylation and expression networks via eQTMs improves prediction of functional gene-gene associations

2021 ◽  
Author(s):  
Shuang Li ◽  
Cancan Qi ◽  
Patrick Deelen ◽  
Floranne Boulogne ◽  
Niek de Klein ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Gene Networks ◽  
Prediction Models ◽  
Meta Analysis ◽  
Rna Seq ◽  
Integrated Network ◽  
Functional Relationships ◽  
Cpg Sites ◽  
Molecular Phenotypes ◽  
Public Datasets

Gene co-expression networks can be used to infer functional relationships between genes, but they do not work well for all genes. We investigated whether DNA methylation can provide complementary information for such genes. We first carried out an eQTM meta-analysis of 3,574 gene expression and methylation samples from blood, brain and nasal epithelial brushed cells to identify links between methylated CpG sites and genes. This revealed 6,067 significant eQTM genes, and we observed that histone modification information is predictive of both eQTM direction and presence, enabling us to link many CpG sites to genes. We then generated a co-methylation network - MethylationNetwork - using 27,720 publicly available methylation profiles and integrated it with a public RNA-seq co-expression dataset of 31,499 samples. Here, we observed that MethylationNetwork can identify experimentally validated interacting pairs of genes that could not be identified in the RNA-seq datasets. We then developed a novel integration pipeline based on CCA and used the integrated methylation and gene networks to predict gene pairs reported in the STRING database. The integrated network showed significantly improved prediction performance compared to using a DNA co-methylation or a gene co-expression network alone. This is the first study to integrate data from two -omics layers from unmatched public samples across different tissues and diseases, and our results highlight the issues and potential of integrating public datasets from multiple molecular phenotypes. The eQTMs we identified can be used as an annotation resource for epigenome-wide association, and we believe that our integration pipeline can be used as a framework for future -omics integration analyses of public datasets. We provide supporting materials and results, including the harmonized DNA methylation data from multiple tissues and diseases in https://data.harmjanwestra.nl/comethylation/, the discovered and predicted eQTMs, the corresponding CCA components and the trained prediction models in a Zenodo repository (https://zenodo.org/record/4666994). We provide notebooks to facilitate use of the proposed pipeline in a GitHub repository (https://github.com/molgenis/methylationnetwork).

A Tissue Comparison of DNA Methylation of the Glucocorticoid Receptor Gene (Nr3c1) in European Starlings

2019 ◽  
Vol 59 (2) ◽  
pp. 264-272 ◽  
Author(s):  
Stefanie J Siller ◽  
Dustin R Rubenstein
Keyword(s):  
Dna Methylation ◽  
Glucocorticoid Receptor ◽  
Glucocorticoid Receptors ◽  
Epigenetic Modification ◽  
Receptor Gene ◽  
Putative Promoter ◽  
European Starlings ◽  
Cpg Sites ◽  
Glucocorticoid Receptor Gene ◽  
The Brain

Abstract Negative feedback of the vertebrate stress response via the hypothalamic–pituitary–adrenal (HPA) axis is regulated by glucocorticoid receptors in the brain. Epigenetic modification of the glucocorticoid receptor gene (Nr3c1), including DNA methylation of the promoter region, can influence expression of these receptors, impacting behavior, physiology, and fitness. However, we still know little about the long-term effects of these modifications on fitness. To better understand these fitness effects, we must first develop a non-lethal method to assess DNA methylation in the brain that allows for multiple measurements throughout an organism’s lifetime. In this study, we aimed to determine if blood is a viable biomarker for Nr3c1 DNA methylation in two brain regions (hippocampus and hypothalamus) in adult European starlings (Sturnus vulgaris). We found that DNA methylation of CpG sites in the complete Nr3c1 putative promoter varied among tissue types and was lowest in blood. Although we identified a similar cluster of correlated Nr3c1 putative promoter CpG sites within each tissue, this cluster did not show any correlation in DNA methylation among tissues. Additional studies should consider the role of the developmental environment in producing epigenetic modifications in different tissues.

scholarly journals Increases in Bdnf DNA Methylation in the Prefrontal Cortex Following Aversive Caregiving Are Reflected in Blood Tissue

2020 ◽  
Vol 14 ◽  
Author(s):  
Hannah B. D. Duffy ◽  
Tania L. Roth
Keyword(s):  
Dna Methylation ◽  
Prefrontal Cortex ◽  
Child Maltreatment ◽  
Mental Disorders ◽  
Neurotrophic Factor ◽  
Aberrant Methylation ◽  
Epigenetic Changes ◽  
Behavioral Deficits ◽  
Peripheral Tissues ◽  
The Brain

Child maltreatment not only leads to epigenetic changes, but also increases the risk of related behavioral deficits and mental disorders. These issues presumably are most closely associated with epigenetic changes in the brain, but epigenetic changes in peripheral tissues like blood are often examined instead, due to their accessibility. As such, the reliability of using the peripheral epigenome as a proxy for that of the brain is imperative. Previously, our lab has found aberrant methylation at the Brain-derived neurotrophic factor (Bdnf) gene in the prefrontal cortex of rats following aversive caregiving. The current study examined whether aversive caregiving alters Bdnf DNA methylation in the blood compared to the prefrontal cortex. It was revealed that DNA methylation associated with adversity increased in both tissues, but this methylation was not correlated between tissues. These findings indicate that group trends in Bdnf methylation between blood and the brain are comparable, but variation exists among individual subjects.

scholarly journals Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies novel methylation loci

2019 ◽  
Author(s):  
Alicia K Smith ◽  
Andrew Ratanatharathorn ◽  
Adam X Maihofer ◽  
Robert K Naviaux ◽  
Allison E Aiello ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stress Disorder ◽  
Smoking Status ◽  
Meta Analysis ◽  
Biological Processes ◽  
Metabolomics Data ◽  
Cpg Sites ◽  
Aryl Hydrocarbon ◽  
Analysis Strategy ◽  
Insight Into

AbstractDifferences in susceptibility to posttraumatic stress disorder (PTSD) may be related to epigenetic differences between PTSD cases and trauma-exposed controls. Such epigenetic differences may provide insight into the biological processes underlying the disorder. Here we describe the results of the largest DNA methylation meta-analysis of PTSD to date with data from the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup. Ten cohorts, military and civilian, contributed blood-derived DNA methylation data (HumanMethylation450 BeadChip) from 1,896 PTSD cases (42%) and trauma-exposed controls (58%). Utilizing a common QC and analysis strategy, we identified ten CpG sites associated with PTSD (9.61E-07<p<4.72E-11) after adjustment for multiple comparisons (FDR<.05). Several CpGs were located in genes previously implicated in PTSD and other psychiatric disorders. The top four CpG sites fell within the aryl-hydrocarbon receptor repressor (AHRR) locus and were associated with lower DNA methylation in PTSD cases relative to controls. Interestingly, this association appeared to uncorrelated with smoking status and was most pronounced in non-smokers with PTSD. Additional evaluation of metabolomics data supported our findings and revealed that AHRR methylation associated with kynurenine levels, which were lower among subjects with PTSD relative to controls. Overall, this study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

scholarly journals A correlation map of genome-wide DNA methylation patterns between paired human brain and buccal samples

2021 ◽  
Author(s):  
Yasmine Sommerer ◽  
Olena Ohlei ◽  
Valerija Dobricic ◽  
Derek H. Oakley ◽  
Tanja Wesse ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Prefrontal Cortex ◽  
Association Studies ◽  
Promoter Regions ◽  
Functional Interpretation ◽  
Peripheral Tissues ◽  
Cpg Sites ◽  
Dorsolateral Prefrontal ◽  
Significant Enrichment ◽  
Methylation Patterns

Epigenome-wide association studies (EWAS) assessing the link between DNA methylation (DNAm) and phenotypes related to structural brain measures, cognitive function, and neurodegenerative diseases are becoming increasingly more popular. Due to the inaccessibility of brain tissue in humans, several studies use peripheral tissues such as blood, buccal swabs, and saliva as surrogates. To aid the functional interpretation of EWAS findings in such settings, there is a need to assess the correlation of DNAm variability across tissues in the same individuals. In this study, we performed a correlation analysis between DNAm data of a total of n=120 matched post-mortem buccal and prefrontal cortex samples. We identified nearly 25,000 (3% of approximately 730,000) cytosine-phosphate-guanine (CpG) sites showing significant (False Discovery Rate q < 0.05) correlations between buccal and PFC samples. Correlated CpG sites showed a preponderance to being located in promoter regions and showed a significant enrichment of being determined by genetic factors, i.e. methylation quantitative trait loci (mQTL), based on buccal and dorsolateral prefrontal cortex mQTL databases. Our novel buccal-brain DNAm correlation map will provide a valuable resource for future EWAS using buccal samples for studying DNAm effects on phenotypes relating to the brain. All correlation results are made freely available to the public online.

scholarly journals Peripheral blood DNA methylation and autism spectrum disorder

2018 ◽  
Author(s):  
Shan V. Andrews ◽  
Brooke Sheppard ◽  
Gayle C. Windham ◽  
Laura A. Schieve ◽  
Diana E. Schendel ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Sample Size ◽  
Meta Analysis ◽  
Autism Spectrum ◽  
Case Control ◽  
Small Sample ◽  
Spectrum Disorder ◽  
Blood Samples ◽  
Cpg Sites

AbstractBackgroundSeveral reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size, and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies.MethodsDNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample.FindingsIn this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p < 1.12×10−7. Seven CpGs showed differences at p < 1×10−5 and 48 at 1×10−4. Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance (r = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpGs hits, which was consistent across EWAS and meQTL discovery p-value thresholds.ConclusionsWe report the largest case-control EWAS study of ASD to date. No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the 7 sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD.

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