scholarly journals Autism-Associated DNA Methylation at Birth From Multiple Tissues Is Enriched for Autism Genes in the Early Autism Risk Longitudinal Investigation

2021 ◽  
Vol 14 ◽  
Author(s):  
Kelly M. Bakulski ◽  
John F. Dou ◽  
Jason I. Feinberg ◽  
Max T. Aung ◽  
Christine Ladd-Acosta ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Late Pregnancy ◽  
Maternal Blood ◽  
Autism Spectrum ◽  
Epigenetic Mark ◽  
Global Methylation ◽  
Risk Genes ◽  
Longitudinal Investigation ◽  
Research Initiative

Background: Pregnancy measures of DNA methylation, an epigenetic mark, may be associated with autism spectrum disorder (ASD) development in children. Few ASD studies have considered prospective designs with DNA methylation measured in multiple tissues and tested overlap with ASD genetic risk loci.Objectives: To estimate associations between DNA methylation in maternal blood, cord blood, and placenta and later diagnosis of ASD, and to evaluate enrichment of ASD-associated DNA methylation for known ASD-associated genes.Methods: In the Early Autism Risk Longitudinal Investigation (EARLI), an ASD-enriched risk birth cohort, genome-scale maternal blood (early n = 140 and late n = 75 pregnancy), infant cord blood (n = 133), and placenta (maternal n = 106 and fetal n = 107 compartments) DNA methylation was assessed on the Illumina 450k HumanMethylation array and compared to ASD diagnosis at 36 months of age. Differences in site-specific and global methylation were tested with ASD, as well as enrichment of single site associations for ASD risk genes (n = 881) from the Simons Foundation Autism Research Initiative (SFARI) database.Results: No individual DNA methylation site was associated with ASD at genome-wide significance, however, individual DNA methylation sites nominally associated with ASD (P < 0.05) in each tissue were highly enriched for SFARI genes (cord blood P = 7.9 × 10–29, maternal blood early pregnancy P = 6.1 × 10–27, maternal blood late pregnancy P = 2.8 × 10–16, maternal placenta P = 5.6 × 10–15, fetal placenta P = 1.3 × 10–20). DNA methylation sites nominally associated with ASD across all five tissues overlapped at 144 (29.5%) SFARI genes.Conclusion: DNA methylation sites nominally associated with later ASD diagnosis in multiple tissues were enriched for ASD risk genes. Our multi-tissue study demonstrates the utility of examining DNA methylation prior to ASD diagnosis.

scholarly journals LINE-1 and Alu methylation Signatures in Autism Spectrum Disorder and Their Function in The Regulation of Autism-Related Genes

2021 ◽  
Author(s):  
Thanit Saeliw ◽  
Tiravut Permpoon ◽  
Nutta Iadsee ◽  
Tewin Tencomnao ◽  
Tewarit Sarachana ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Autism Spectrum ◽  
Small Sample ◽  
Spectrum Disorder ◽  
Post Mortem ◽  
Global Methylation ◽  
Post Mortem Brain ◽  
Dna Methylation Profiling ◽  
Methylation Profiling

Abstract BackgroundLong interspersed nucleotide element-1 (LINE-1) and Alu elements are retrotransposons whose abilities cause abnormal gene expression and genomic instability. Several studies have focused on DNA methylation profiling of gene regions, but the locus-specific methylation of LINE-1 and Alu elements has not been identified in autism spectrum disorder (ASD).MethodsHere, DNA methylation age was predicted using Horvath’s method. We interrogated locus- and family-specific methylation profiles of LINE-1 and Alu elements (22,352 loci) in ASD blood using publicly-available Illumina Infinium 450K methylation datasets from heterogeneous ASD (n = 52), ASD with 16p11.2 del (n = 7), and ASD with Chromodomain Helicase DNA-binding 8 (CHD8) variants (n = 15). The differentially methylated positions of LINE-1 and Alu elements corresponding to genes were combined with transcriptome data from multiple ASD studies. ROC curve was conducted to examine the specificity of target loci.ResultsEpigenetic age acceleration was significantly decelerated in ASD children over the age of 11 years. DNA methylation profiling revealed LINE-1 and Alu methylation signatures in each ASD risk loci by which global methylation were notably hypomethylated exclusively in ASD with CHD8 variants. When LINE-1 and Alu elements were clustered into subfamilies, we found methylation changes in a family-specific manner in L1P, L1H, HAL, AluJ, and AluS families in the heterogeneous ASD and ASD with CHD8 variants. Our results showed that LINE-1 and Alu methylation within target genes is inversely related to the expression level in each ASD variant. Moreover, LINE-1 and Alu methylation signatures can be used to predict ASD individuals from non-ASD.LimitationsIntegration of methylome and transcriptome datasets was performed from different ASD cohorts. The small sample size of the validation cohort used post-mortem brain tissues and necessitates future validation in a larger cohort.ConclusionsThe DNA methylation signatures of the LINE-1 and Alu elements in ASD, as well as their functional impact on ASD-related genes, have been studied. These findings are considered for further research into DNA methylation profiles and the expression of the LINE-1 and Alu elements in post-mortem brain tissue, which has been linked to ASD pathogenesis.

Abstract P133: Epigenome-Wide Association Study of Moderate-Vigorous Physical Activity in Adult African Americans Identifies Loci Near HCCA2

Circulation ◽  
2018 ◽  
Vol 137 (suppl_1) ◽  
Author(s):  
Steven Nguyen ◽  
Weihua Guan ◽  
Chong Wu ◽  
Megan Grove ◽  
Rui Xia ◽  
...  
Keyword(s):  
Physical Activity ◽  
Dna Methylation ◽  
Leisure Time ◽  
Acute Exercise ◽  
Association Studies ◽  
Vigorous Physical Activity ◽  
Genomic Region ◽  
Epigenetic Mark ◽  
Global Methylation ◽  
Exercise Interventions

Regular moderate-vigorous physical activity (MVPA) reduces the risk of cardiovascular and other chronic diseases, among other important benefits at all life stages. It is hypothesized that physical activity may alter disease risk via epigenetic modifications, including potentially long-standing changes in DNA methylation as previous research has shown epigenetic changes following exercise interventions. Most existing reports examine global methylation or study acute exercise effects on DNA methylation. To our knowledge, there are no published epigenome-wide association studies (EWAS) of habitual MVPA. In this analysis, we tested associations between leisure time MVPA and genome-wide variation in CpG methylation, an epigenetic mark, in 2,601 African American participants (1,663 women; mean age 56.6 years) in the Atherosclerosis Risk in Communities (ARIC) study. The Illumina HM450K Bead Chip was used to measure methylation in 471,035 CpG sites in stored frozen leukocyte samples, from visit 2 (1990-1992) or 3 (1993-1995). Linear regression models tested the cross-sectional association of DNA methylation M-value with self-reported leisure time MVPA at the visit of sample collection, modeled as minutes of MVPA per week and by category based on the AHA guidelines for physical activity in adults (none, less than 150, or at least 150 minutes MVPA per week), adjusting for age, sex, body mass index, education, alcohol use in grams per week, smoking status, cancer status, white blood cell count, imputed cell-type proportions using the Houseman method, and batch effects with the top 30 HM450K built-in nonnegative control probe principal components. Three CpGs, cg08269485, cg20272155, and cg08966208, upstream of the cathepsin D encoding gene, CTSD, were observed to be significantly inversely associated (q<0.05, FDR) with MVPA minutes/week. This is a strongly imprinted genomic region (chr11p15.5) and the region has also been reported to include DNA methylation variants that changed in response to an exercise training intervention. Additionally, 163 CpGs that we identified in the literature to be associated with habitual MVPA were also tested using the same models. One CpG, cg07863043, upstream of the adenomatosis polyposis coli gene, APC, in the 5q22.2 genomic region, was observed to be significantly positively associated with achieving at least 150 minutes of MVPA per week compared to none (q=0.0001, FDR). APC encodes a tumor suppressor protein that is an antagonist of the Wnt signaling pathway, and is involved in carcinogenesis and embryonic development. Replication in other populations is ongoing to confirm these findings as well as to identify additional physical activity-related DNA methylation variants.

scholarly journals Maternal blood metal concentrations and whole blood DNA methylation during pregnancy in the Early Autism Risk Longitudinal Investigation (EARLI)

2020 ◽  
Author(s):  
Max T. Aung ◽  
Kelly M. Bakulski ◽  
Jason I. Feinberg ◽  
John F. Dou ◽  
John D. Meeker ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Linear Regression ◽  
Whole Blood ◽  
Maternal Blood ◽  
Nervous System Development ◽  
Q Value ◽  
450K Array ◽  
Smoking During Pregnancy ◽  
Longitudinal Investigation ◽  
Cadmium Lead

AbstractBackgroundMetals exposures have important health effects in pregnancy. The maternal epigenome may be responsive to these exposures. We tested whether metals are associated with concurrent differential maternal whole blood DNA methylation.MethodsIn the Early Autism Risk Longitudinal Investigation (EARLI) cohort, we measured first or second trimester maternal blood metals concentrations (cadmium, lead, mercury, manganese, and selenium) in 215 participants using inductively coupled plasma mass spectrometry. DNA methylation in maternal whole blood was measured in the same specimens on the Illumina 450K array (201 participants). A subset sample of 97 women had both measures available for analysis, all of whom did not report smoking during pregnancy. Linear regression was used to test for site-specific associations between individual metals and DNA methylation, adjusting for cell type composition and confounding variables. Discovery gene ontology analysis was conducted on the top 1,000 sites associated with each metal to elucidate downstream pathways.ResultsIn multiple linear regression, we observed hypermethylation at 11 DNA methylation sites associated with lead (FDR q-value <0.1), near the genes CYP24A1, ASCL2, FAT1, SNX31, NKX6-2, LRC4C, BMP7, HOXC11, PCDH7, ZSCAN18, and VIPR2. Lead associated sites were enriched (FDR q-value <0.1) for the pathways cell adhesion, nervous system development, and calcium ion binding. Manganese was associated with hypermethylation at four DNA methylation sites (FDR q-value <0.1), one of which was near the gene ARID2. Manganese associated sites were enriched for cellular metabolism pathways (FDR q-value<0.1). Effect estimates for DNA methylation sites associated (p<0.05) with cadmium, lead, and manganese were highly correlated (Pearson ρ >0.86).DiscussionSingle DNA methylation sites associated with lead and manganese may be potential biomarkers of exposure or implicate downstream gene pathways. Future studies should replicate our findings to characterize potential toxicological mechanisms of trace metals through the maternal epigenome.

scholarly journals Methyl-CpG binding domain 2 (Mbd2) is an Epigenetic Regulator of Autism-Risk Genes and Cognition

2018 ◽  
Author(s):  
Elad Lax ◽  
Sonia DoCarmo ◽  
Yehoshua Enuka ◽  
Daniel M. Sapozhnikov ◽  
Lindsay A. Welikovitch ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Autism Spectrum ◽  
Methylation Pattern ◽  
Binding Domain ◽  
Behavioral Alterations ◽  
Risk Genes ◽  
A Genome ◽  
Epigenetic Regulator ◽  
Neuronal Genes ◽  
Regulatory Dna

AbstractThe Methyl-CpG-Binding Domain Protein family has been implicated in neurodevelopmental disorders. The Methyl-CpG-binding domain 2 (Mbd2) binds methylated DNA and was shown to play an important role in cancer and immunity. Some evidence linked this protein to neurodevelopment. However, its exact role in neurodevelopment and brain function is mostly unknown.Here we show that Mbd2-deficiency in mice (Mbd2−/−) results in deficits in cognitive, social and emotional functions. Mbd2 binds regulatory DNA regions of neuronal genes in the hippocampus and loss of Mbd2 alters the expression of hundreds of genes with a robust down-regulation of neuronal gene pathways. Further, a genome-wide DNA methylation analysis found an altered DNA methylation pattern in regulatory DNA regions of neuronal genes in Mbd2−/− mice. Differentially expressed genes significantly overlap with gene-expression changes observed in brains of Autism Spectrum Disorder (ASD) individuals. Notably, down-regulated genes are significantly enriched for human ortholog ASD risk-genes. Observed hippocampal morphological abnormalities were similar to those found in individuals with ASD and ASD rodent models. Hippocampal Mbd2 knockdown partially recapitulates the behavioral phenotypes observed in Mbd2−/− mice.These findings suggest Mbd2 is a novel epigenetic regulator of genes that are associated with ASD in humans. Mbd2 loss causes behavioral alterations that resemble those found in ASD individuals.

Exercise intervention during pregnancy induces promoter methylation alterations in cord blood

2020 ◽  
Author(s):  
Jie Yan ◽  
Chen Wang ◽  
Yumei Wei ◽  
Huixia Yang
Keyword(s):  
Dna Methylation ◽  
Exercise Training ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Maternal Blood ◽  
In Utero ◽  
Exercise Group ◽  
Sensitive Period ◽  
Control Group

Abstract Background: Environmental events and nutritional conditions may induce permanent DNA methylation changes in utero during the sensitive period and these adaptive changes may be ‘memorized’ and have a lasting impact on adult disease later in life. The potential plasticity of DNA methylation also enables reprogramming, depending on exposure to nutritional, chemical, and environmental factors. We determined the effects of exercise training during pregnancy on epigenetic modifications in offspring.Results: Twenty-four subjects were chosen from a previous clinical study. Overweight/obese pregnant women (body mass index <28/≥28kg/m2) who had an uncomplicated pregnancy at <12+6 weeks of gestation were randomly allocated to either an exercise or a control group. Patients allocated to the exercise group performed 3 exercise bouts per week (at least 30 min/session with a rating of perceived exertion between 12-14) via a cycling program that was initiated within 3 days of randomization until 37 weeks of gestation. Patients allocated to the control group continued their usual daily activities. Maternal blood, as well as umbilical cord blood samples, were collected and DNA methylation levels were determined by Illumina MethylationEPIC microarray. Nine CpG sites and corresponding genes UMAD1, RPA3, PLAGL2, POFUT1, SPATA17, GPATCH2, CEP170, MPHOSPH10, MCEE, as well as MRGPRD showed differential trends in control and exercise groups in maternal blood. Furthermore, four specific genes in umbilical cord blood were differentially methylated in the exercise group compared to the sedentary controls (p < 0.01). Conclusions: DNA methylation in maternal blood is dynamically altered during pregnancy and remodeled by exercise training. Thus, intrauterine environmental exposures play an important role in fetal programming. Epigenetic mechanisms involving changes in DNA methylation may provide an explanation for the phenomenon. Our findings shed light on understanding of long-term effects of in utero exposures on the epigenetic landscape of the offspring.

Associations between maternal prenatal stress, methylation changes in IGF1 and IGF2, and birth weight

2017 ◽  
Vol 9 (2) ◽  
pp. 215-222 ◽  
Author(s):  
D. Montoya-Williams ◽  
J. Quinlan ◽  
C. Clukay ◽  
N. C. Rodney ◽  
D. A. Kertes ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Birth Weight ◽  
Low Birth Weight ◽  
Cord Blood ◽  
Prenatal Stress ◽  
Maternal Stress ◽  
Democratic Republic Of Congo ◽  
Placental Tissue ◽  
Maternal Blood ◽  
Tissue Samples

Maternal stress has been linked to low birth weight in newborns. One potential pathway involves epigenetic changes at candidate genes that may mediate the effects of prenatal maternal stress on birth weight. This relationship has been documented in stress-related genes, such as NR3C1. There is less literature exploring the effect of stress on growth-related genes. IGF1 and IGF2 have been implicated in fetal growth and development, though via different mechanisms as IGF2 is under imprinting control. In this study, we tested for associations between prenatal stress, methylation of IGF1 and IGF2, and birth weight. A total of 24 mother–newborn dyads in the Democratic Republic of Congo were enrolled. Ethnographic interviews were conducted with mothers at delivery to gather culturally relevant war-related and chronic stressors. DNA methylation data were generated from maternal venous, cord blood and placental tissue samples. Multivariate regressions were used to test for associations between stress measures, DNA methylation and birth weight in each of the three tissue types. We found an association between IGF2 methylation in maternal blood and birth weight. Previous literature on the relationship between IGF2 methylation and birth weight has focused on methylation at known differentially methylated regions in cord blood or placental samples. Our findings indicate there may be links between the maternal epigenome and low birth weight that rely on mechanisms outside known imprinting pathways. It thus may be important to consider the effect of maternal exposures and epigenetic profiles on birth weight even in the setting of maternally imprinted genes such as IGF2.

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