Leukocyte methylomic imprints of exposure to the genocide against the Tutsi in Rwanda: a pilot epigenome-wide analysis

We conducted a pilot epigenome-wide association study of women from Tutsi ethnicity exposed to the genocide while pregnant and their resulting offspring, and a comparison group of women who were pregnant at the time of the genocide but living outside of Rwanda. Fifty-nine leukocyte-derived DNA samples survived quality control: 33 mothers (20 exposed, 13 unexposed) and 26 offspring (16 exposed, 10 unexposed). Twenty-four significant differentially methylated regions (DMRs) were identified in mothers and 16 in children. In utero genocide exposure was associated with CpGs in three of the 24 DMRs: BCOR, PRDM8 and VWDE, with higher DNA methylation in exposed versus unexposed offspring. Of note, BCOR and VWDE show significant correlation between brain and blood DNA methylation within individuals, suggesting these peripherally derived signals of genocide exposure may have relevance to the brain.

The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis

Nature Communications ◽

10.1038/s41467-021-21064-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ivo S. Muskens ◽

Shaobo Li ◽

Thomas Jackson ◽

Natalina Elliot ◽

Helen M. Hansen ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Down Syndrome ◽

Association Study ◽

Fetal Liver ◽

Hematopoietic Stem ◽

Minimal Impact ◽

Genome Wide ◽

Study Results

AbstractDown syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P < 7.67 × 10−8) and 1,052 differentially methylated regions. Differential methylation at promoter/enhancer regions correlates with gene expression changes in Down syndrome versus non-Down syndrome fetal liver hematopoietic stem/progenitor cells (P < 0.0001). The top two differentially methylated regions overlap RUNX1 and FLI1, both important regulators of megakaryopoiesis and hematopoietic development, with significant hypermethylation at promoter regions of these two genes. Excluding Down syndrome newborns harboring preleukemic GATA1 mutations (N = 30), identified by targeted sequencing, has minimal impact on the epigenome-wide association study results. Down syndrome has profound, genome-wide effects on DNA methylation in hematopoietic cells in early life, which may contribute to the high frequency of hematological problems, including leukemia, in children with Down syndrome.

Human brain region-specific variably methylated regions are enriched for heritability of distinct neuropsychiatric traits

Genome Biology ◽

10.1186/s13059-021-02335-w ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Lindsay F. Rizzardi ◽

◽

Peter F. Hickey ◽

Adrian Idrizi ◽

Rakel Tryggvadóttir ◽

...

Keyword(s):

Dna Methylation ◽

Human Brain ◽

Brain Region ◽

Pairwise Comparison ◽

Brain Regions ◽

Differential Methylation ◽

Anterior Cingulate ◽

Neuronal Nuclei ◽

Abstract Background DNA methylation dynamics in the brain are associated with normal development and neuropsychiatric disease and differ across functionally distinct brain regions. Previous studies of genome-wide methylation differences among human brain regions focus on limited numbers of individuals and one to two brain regions. Results Using GTEx samples, we generate a resource of DNA methylation in purified neuronal nuclei from 8 brain regions as well as lung and thyroid tissues from 12 to 23 donors. We identify differentially methylated regions between brain regions among neuronal nuclei in both CpG (181,146) and non-CpG (264,868) contexts, few of which were unique to a single pairwise comparison. This significantly expands the knowledge of differential methylation across the brain by 10-fold. In addition, we present the first differential methylation analysis among neuronal nuclei from basal ganglia tissues and identify unique CpG differentially methylated regions, many associated with ion transport. We also identify 81,130 regions of variably CpG methylated regions, i.e., variable methylation among individuals in the same brain region, which are enriched in regulatory regions and in CpG differentially methylated regions. Many variably methylated regions are unique to a specific brain region, with only 202 common across all brain regions, as well as lung and thyroid. Variably methylated regions identified in the amygdala, anterior cingulate cortex, and hippocampus are enriched for heritability of schizophrenia. Conclusions These data suggest that epigenetic variation in these particular human brain regions could be associated with the risk for this neuropsychiatric disorder.

Genome-wide DNA methylation analyses in the brain reveal four differentially methylated regions between humans and non-human primates

BMC Evolutionary Biology ◽

10.1186/1471-2148-12-144 ◽

2012 ◽

Vol 12 (1) ◽

pp. 144 ◽

Cited By ~ 11

Author(s):

Jinkai Wang ◽

Xiangyu Cao ◽

Yanfeng Zhang ◽

Bing Su

Keyword(s):

Dna Methylation ◽

Genome Wide ◽

Exposure to Low Levels of Lead in Utero and Umbilical Cord Blood DNA Methylation in Project Viva: An Epigenome-Wide Association Study

Environmental Health Perspectives ◽

10.1289/ehp1246 ◽

2017 ◽

Vol 125 (8) ◽

pp. 087019 ◽

Cited By ~ 27

Author(s):

Shaowei Wu ◽

Marie-France Hivert ◽

Andres Cardenas ◽

Jia Zhong ◽

Sheryl L. Rifas-Shiman ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Association Study ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

In Utero ◽

Low Levels

DNA methylation of BDNF as a biomarker of early-life adversity

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1408355111 ◽

2014 ◽

Vol 112 (22) ◽

pp. 6807-6813 ◽

Cited By ~ 182

Author(s):

Marija Kundakovic ◽

Kathryn Gudsnuk ◽

Julie B. Herbstman ◽

Deliang Tang ◽

Frederica P. Perera ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Environmental Exposure ◽

Early Life ◽

Later Life ◽

Underlying Mechanism ◽

In Utero ◽

Long Term Effects ◽

Early Life Adversity ◽

Early-life adversity increases the risk for psychopathology in later life. The underlying mechanism(s) is unknown, but epigenetic variation represents a plausible candidate. Early-life exposures can disrupt epigenetic programming in the brain, with lasting consequences for gene expression and behavior. This evidence is primarily derived from animal studies, with limited study in humans due to inaccessibility of the target brain tissue. In humans, although there is evidence for DNA methylation changes in the peripheral blood of psychiatric patients, a fundamental question remains as to whether epigenetic markers in the blood can predict epigenetic changes occurring in the brain. We used in utero bisphenol A (BPA) exposure as a model environmental exposure shown to disrupt neurodevelopment and exert long-term effects on behavior in animals and humans. We show that prenatal BPA induces lasting DNA methylation changes in the transcriptionally relevant region of the Bdnf gene in the hippocampus and blood of BALB/c mice and that these changes are consistent with BDNF changes in the cord blood of humans exposed to high maternal BPA levels in utero. Our data suggest that BDNF DNA methylation in the blood may be used as a predictor of brain BDNF DNA methylation and gene expression as well as behavioral vulnerability induced by early-life environmental exposure. Because BDNF expression and DNA methylation are altered in several psychiatric disorders that are associated with early-life adversity, including depression, schizophrenia, bipolar disorder, and autism, BDNF DNA methylation in the blood may represent a novel biomarker for the early detection of psychopathology.

Family-based Association Study Between the Brain Derived Neurotrophic Factor (BDNF) Gene and the Attention Deficit Hyperactivity Disorder in a Mexican Population

10.26226/morressier.58a41cf6d462b8028d892521 ◽

2017 ◽

Author(s):

Juan Pablo Sánchez de la Cruz

Keyword(s):

Attention Deficit Hyperactivity Disorder ◽

Association Study ◽

Attention Deficit ◽

Neurotrophic Factor ◽

Brain Derived Neurotrophic Factor ◽

Mexican Population ◽

Bdnf Gene ◽

Hyperactivity Disorder ◽

Family Based ◽

DNA Methylation Profiles of Tph1A and BDNF in Gut and Brain of L. Rhamnosus-Treated Zebrafish

Biomolecules ◽

10.3390/biom11020142 ◽

2021 ◽

Vol 11 (2) ◽

pp. 142

Author(s):

Mariella Cuomo ◽

Luca Borrelli ◽

Rosa Della Monica ◽

Lorena Coretti ◽

Giulia De Riso ◽

...

Keyword(s):

Dna Methylation ◽

Molecular Mechanisms ◽

The Past ◽

Targeted Analysis ◽

Lack Of Information ◽

High Resolution Power ◽

Resolution Level ◽

Health And Disease ◽

High Doses ◽

The bidirectional microbiota–gut–brain axis has raised increasing interest over the past years in the context of health and disease, but there is a lack of information on molecular mechanisms underlying this connection. We hypothesized that change in microbiota composition may affect brain epigenetics leading to long-lasting effects on specific brain gene regulation. To test this hypothesis, we used Zebrafish (Danio Rerio) as a model system. As previously shown, treatment with high doses of probiotics can modulate behavior in Zebrafish, causing significant changes in the expression of some brain-relevant genes, such as BDNF and Tph1A. Using an ultra-deep targeted analysis, we investigated the methylation state of the BDNF and Tph1A promoter region in the brain and gut of probiotic-treated and untreated Zebrafishes. Thanks to the high resolution power of our analysis, we evaluated cell-to-cell methylation differences. At this resolution level, we found slight DNA methylation changes in probiotic-treated samples, likely related to a subgroup of brain and gut cells, and that specific DNA methylation signatures significantly correlated with specific behavioral scores.

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

Clinical Epigenetics ◽

10.1186/s13148-021-01041-5 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Chen Yao ◽

Roby Joehanes ◽

Rory Wilson ◽

Toshiko Tanaka ◽

Luigi Ferrucci ◽

...

Keyword(s):

Gene Expression ◽

Lung Cancer ◽

Dna Methylation ◽

Cigarette Smoking ◽

Association Study ◽

Whole Blood ◽

Lung Diseases ◽

Epigenetic Modification ◽

Blood Gene Expression ◽

Increased Risk

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