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

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.

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

2019 ◽  
Author(s):  
Alexander Neumann ◽  
Esther Walton ◽  
Silvia Alemany ◽  
Charlotte Cecil ◽  
Juan Ramon González ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Association Studies ◽  
Meta Analysis ◽  
School Age ◽  
Adhd Symptoms ◽  
Future Studies ◽  
Hyperactivity Disorder ◽  
Causal Pathways ◽  
Nominal Significance ◽  
Age Range

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 not known. 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 DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age range 4-15 years) in 2477 children from five cohorts and DNA methylation at school-age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from ten cohorts. 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 were associated with later ADHD symptoms (P<1*10−7), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 located in the promotor region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which was associated with neurite outgrowth and an ADHD diagnosis in previous studies. 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.

scholarly journals Prenatal Opioid Exposure and ADHD Childhood Symptoms: A Meta-Analysis

Children ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. 106
Author(s):  
Ashlyn N. Schwartz ◽  
Lucia M. Reyes ◽  
Laurie L. Meschke ◽  
Kristina W. Kintziger
Keyword(s):  
Meta Analysis ◽  
Future Research ◽  
School Age ◽  
Adhd Symptoms ◽  
Inclusion Criteria ◽  
Hyperactivity Disorder ◽  
Increased Risk ◽  
Symptom Scores ◽  
Sample Characteristics ◽  
The Relationship

To systematically investigate the association between prenatal opioid exposure (POE) and attention-deficit hyperactivity disorder (ADHD) symptoms in children 2–18 years old, studies were searched using PubMed, CINAHL, PsycINFO, and Web of Science from January of 1950 to October of 2019. Inclusion criteria were observational studies reporting ADHD symptoms of children with POE compared with non-exposed children or normative data. The study protocol was registered with PROSPERO: CRD42018115967. Two independent reviewers extracted data on hyperactivity/impulsivity, inattention symptoms, ADHD combined subscale symptoms, and sample characteristics. Of 223 articles screened, seven met the inclusion criteria. Data represent 319 children with POE and 1308 non-exposed children from 4.3 to 11.2 mean years from five countries. POE was positively associated with childhood hyperactivity/impulsivity (d = 1.40; 95% CI, 0.49–2.31; p = 0.003), inattention (d = 1.35; 95% CI, 0.69–2.01; p < 0.0001), and combined ADHD symptoms scores (d = 1.27; 95% CI = 0.79–1.75; p < 0.0001). POE was positively associated with ADHD combined symptom scores at preschool (d = 0.83, 95% CI, 0.57, 1.09; p < 0.0001) and school age (d = 1.45, 95% CI, 0.85 to 2.04; p < 0.0001). Results suggest increased risk of ADHD symptoms during school age. Future research is needed to clarify the relationship between biological, social, and environmental risk and ADHD symptoms for children who experienced POE.

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 No Evidence That Substance Use Causes ADHD Symptoms in Adolescence

2017 ◽  
Vol 47 (3) ◽  
pp. 405-410 ◽  
Author(s):  
Aja Louise Murray ◽  
Manuel Eisner ◽  
Ingrid Obsuth ◽  
Denis Ribeaud
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Substance Use ◽  
Individual Differences ◽  
Children And Youth ◽  
Adhd Symptoms ◽  
Hyperactivity Disorder ◽  
Causal Pathways ◽  
Substance Use Problems ◽  
The Social ◽  
Lagged Effects

There is a robust association between attention-deficit hyperactivity disorder (ADHD) symptoms and elevated substance use. Several plausible causal pathways from ADHD to substance use have been articulated and supported empirically. In this study, we tested the recent suggestion that substance use could also influence levels of ADHD symptoms. Using the three most recent waves of data from the Zurich Project on the Social Development of Children and Youth (z-proso), we found significant and strong cross-lagged effects of ADHD symptoms on substance use but no significant effects in the opposite direction. This suggests that individual differences in substance use are not related to increases in ADHD symptoms in adolescence. Adolescent-onset symptoms of ADHD are thus unlikely to be caused by substance use, and targeting substance use problems is unlikely to reduce ADHD symptoms.

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

2020 ◽  
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.

scholarly journals Effects of stimulants and atomoxetine on emotional lability in adults: A systematic review and meta-analysis

2017 ◽  
Vol 44 ◽  
pp. 198-207 ◽  
Author(s):  
T.R. Moukhtarian ◽  
R.E. Cooper ◽  
E. Vassos ◽  
P. Moran ◽  
P. Asherson
Keyword(s):  
Systematic Review ◽  
Effect Size ◽  
Meta Analysis ◽  
Emotional Lability ◽  
Adhd Symptoms ◽  
Double Blind ◽  
Hyperactivity Disorder ◽  
Ovid Medline ◽  
Weighted Effect ◽  
The Difference

AbstractBackground:Emotional lability (EL) is an associated feature of attention-deficit/hyperactivity disorder (ADHD) in adults, contributing to functional impairment. Yet the effect of pharmacological treatments for ADHD on EL symptoms is unknown. We conducted a systematic review and meta-analysis to examine the effects of stimulants and atomoxetine on symptoms of EL and compare these with the effects on core ADHD symptoms.Methods:A systematic search was conducted on the databases Embase, PsychInfo, and Ovid Medline®and the clinicaltrials.gov website. We included randomised, double-blind, placebo-controlled trials of stimulants and atomoxetine in adults aged 18–60 years, with any mental health diagnosis characterised by emotional or mood instability, with at least one outcome measure of EL. All identified trials were on adults with ADHD. A random-effects meta-analysis with standardised mean difference and 95% confidence intervals was used to investigate the effect size on EL and compare this to the effect on core ADHD symptoms.Results:Of the 3,864 publications identified, nine trials met the inclusion criteria for the meta-analysis. Stimulants and atomoxetine led to large mean weighted effect-sizes for on ADHD symptoms (n= 9, SMD = −0.8, 95% CI:−1.07 to −0.53). EL outcomes showed more moderate but definite effects (n= 9, SMD = −0.41, 95% CI:−0.57 to −0.25).Conclusions:In this meta-analysis, stimulants and atomoxetine were moderately effective for EL symptoms, while effect size on core ADHD symptoms was twice as large. Methodological issues may partially explain the difference in effect size. Reduced average effect size could also reflect heterogeneity of EL with ADHD pharmacotherapy responsive and non-responsive sub-types. Our findings indicate that EL may be less responsive than ADHD symptoms overall, perhaps indicating the need for adjunctive psychotherapy in some cases. To clarify these questions, our findings need replication in studies selecting subjects for high EL and targeting EL as the primary outcome.

scholarly journals Assessing the Magnitude of Risk for ADHD in Offspring of Parents with ADHD: A Systematic Literature Review and Meta-Analysis

2020 ◽  
pp. 108705472095081
Author(s):  
Mai Uchida ◽  
Haley Driscoll ◽  
Maura DiSalvo ◽  
Aarya Rajalakshmim ◽  
Marco Maiello ◽  
...  
Keyword(s):  
High Risk ◽  
Early Identification ◽  
Meta Analysis ◽  
The Body ◽  
Adhd Symptoms ◽  
Exclusion Criteria ◽  
Hyperactivity Disorder ◽  
Body Of Knowledge ◽  
Increased Risk ◽  
High Risk Children

The main aim of this study was to examine the body of knowledge on the prevalence of Attention Deficit Hyperactivity Disorder (ADHD) in “high-risk” children whose parents are diagnosed with ADHD. This knowledge could aid early identification for children presenting with ADHD symptoms at a young age. We conducted a systematic search of the literature assessing high-risk children. Included were original articles published in English with the main aim to assess prevalence of ADHD in high risk children. In addition, a meta-analysis was conducted to examine this prevalence. Four articles met our inclusion and exclusion criteria all suggesting an increased prevalence of ADHD in children of parents with ADHD. The meta-analysis also confirmed the increased prevalence of ADHD in high-risk children. The literature indicates that children of ADHD parents have an increased risk of developing ADHD compared to control children.

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

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.

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

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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