Prenatal unhealthy diet, insulin-like growth factor 2 gene (IGF2) methylation, and attention deficit hyperactivity disorder symptoms in youth with early-onset conduct problems

Background: Conduct problems (CP) and attention deficit hyperactivity disorder (ADHD) are often comorbid and have each been linked to 'unhealthy diet'. Early-life diet also associates with DNA methylation of the insulin-like growth factor 2 gene (IGF2), involved in fetal and neural development. We investigated the degree to which prenatal high-fat and -sugar diet might relate to ADHD symptoms via IGF2 DNA methylation for early-onset persistent (EOP) versus low CP youth. Methods: Participants were 164 youth with EOP (n = 83) versus low (n = 81) CP drawn from the Avon Longitudinal Study of Parents and Children. We assessed if the interrelationships between high-fat and -sugar diet (prenatal, postnatal), IGF2 methylation (birth and age 7, collected from blood), and ADHD symptoms (age 7-13) differed for EOP versus low CP youth. Results: Prenatal 'unhealthy diet' was positively associated with IGF2 methylation at birth for both the EOP and low CP youth. For EOP only: (a) higher IGF2 methylation predicted ADHD symptoms; and (b) prenatal 'unhealthy diet' was associated with higher ADHD symptoms indirectly via higher IGF2 methylation. Conclusions: Preventing 'unhealthy diet' in pregnancy might reduce the risk of ADHD symptoms in EOP youth via lower offspring IGF2 methylation

Epigenetic profiling of social communication trajectories and co-occurring mental health problems: A prospective, methylome-wide association study

While previous studies suggest that both genetic and environmental factors play an important role in the development of autism-related traits, little is known about potential biological mechanisms underlying these associations. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we examined prospective associations between DNA methylation (DNAm: nbirth = 804, nage 7 = 877) and trajectories of social communication deficits at age 8-17 years. Methylomic variation at three loci across the genome (false discovery rate = 0.048) differentiated children following high (n = 80) versus low (n = 724) trajectories of social communication deficits. This differential DNAm was specific to the neonatal period and not observed at 7 years of age. Associations between DNAm and trajectory membership remained robust after controlling for co-occurring mental health problems (i.e., hyperactivity/inattention, conduct problems). The three loci identified at birth were not replicated in the Generation R Study. However, to the best of our knowledge, ALSPAC is the only study to date that is prospective enough to examine DNAm in relation to longitudinal trajectories of social communication deficits from childhood to adolescence. Although the present findings might point to potentially novel sites that differentiate between a high versus low trajectory of social communication deficits, the results should be considered tentative until further replicated

DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring

Background: We examined whether the effect of maternal smoking during pregnancy on birthweight of the offspring was mediated by smoking-induced changes to DNA methylation in cord blood. Methods: First, we used cord blood of 129 Dutch children exposed to maternal smoking vs 126 unexposed to maternal and paternal smoking (53% male) participating in the GECKO Drenthe birth cohort. DNA methylation was measured using the Illumina HumanMethylation450 Beadchip. We performed an epigenome-wide association study for the association between maternal smoking and methylation followed by a mediation analysis of the top signals [false-discovery rate (FDR)<0.05]. We adjusted both analyses for maternal age, education, pre-pregnancy BMI, offspring's sex, gestational age and white blood cell composition. Secondly, in 175 exposed and 1248 unexposed newborns from two independent birth cohorts, we replicated and meta-analysed results of eight cytosine-phosphate-guanine (CpG) sites in the GFI1 gene, which showed the most robust mediation. Finally, we performed functional network and enrichment analysis. Results: We found 35 differentially methylated CpGs (FDR<0.05) in newborns exposed vs unexposed to smoking, of which 23 survived Bonferroni correction (P<1×10-7). These 23 CpGs mapped to eight genes: AHRR, GFI1, MYO1G, CYP1A1, NEUROG1, CNTNAP2, FRMD4A and LRP5. We observed partial confirmation as three of the eight CpGs in GFI1 replicated. These CpGs partly mediated the effect of maternal smoking on birthweight (Sobel P<0.05) in meta-analysis of GECKO and the two replication cohorts. Differential methylation of these three GFI1 CpGs explained 12-19% of the 202 g lower birthweight in smoking mothers. Functional enrichment analysis pointed towards activation of cell-mediated immunity. Conclusions: Maternal smoking during pregnancy was associated with cord blood methylation differences. We observed a potentially mediating role of methylation in the association between maternal smoking during pregnancy and birthweight of the offspring. Functional network analysis suggested a role in activating the immune system

Epigenomics of being bullied: changes in DNA methylation following bullying exposure

Bullying among children is ubiquitous and associated with pervasive mental health problems. However, little is known about the biological pathways that change after exposure to bullying. Epigenome-wide changes in DNA methylation in peripheral blood were studied from pre- to post measurement of bullying exposure, in a longitudinal study of the population-based Generation R Study and Avon Longitudinal Study of Parents and Children (combined n = 1,352). Linear mixed-model results were meta-analysed to estimate how DNA methylation changed as a function of exposure to bullying. Sensitivity analyses including co-occurring child characteristics and risks were performed, as well as a Gene Ontology analysis. A candidate follow-up was employed for CpG (cytosine-phosphate-guanine) sites annotated to 5-HTT and NR3C1. One site, cg17312179, showed small changes in DNA methylation associated to bullying exposure (b = −2.67e-03, SE = 4.97e-04, p = 7.17e-08). This site is annotated to RAB14, an oncogene related to Golgi apparatus functioning, and its methylation levels decreased for exposed but increased for non-exposed. This result was consistent across sensitivity analyses. Enriched Gene Ontology pathways for differentially methylated sites included cardiac function and neurodevelopmental processes. Top CpG sites tended to have overall low levels of DNA methylation, decreasing in exposed, increasing in non-exposed individuals. There were no gene-wide corrected findings for 5-HTT and NR3C1. This is the first study to identify changes in DNA methylation associated with bullying exposure at the epigenome-wide significance level. Consistent with other population-based studies, we do not find evidence for strong associations between bullying exposure and DNA methylation

Deriving the dietary approaches to stop hypertension (DASH) score in women from seven pregnancy cohorts from the European alphabet consortium

The ALPHABET consortium aims to examine the interplays between maternal diet quality, epigenetics and offspring health in seven pregnancy/birth cohorts from five European countries. We aimed to use the Dietary Approaches to Stop Hypertension (DASH) score to assess diet quality, but different versions have been published. To derive a single DASH score allowing cross-country, cross-cohort and cross-period comparison and limiting data heterogeneity within the ALPHABET consortium, we harmonised food frequency questionnaire (FFQ) data collected before and during pregnancy in ≥26,500 women. Although FFQs differed strongly in length and content, we derived a consortium DASH score composed of eight food components by combining the prescriptive original DASH and the DASH described by Fung et al. Statistical issues tied to the nature of the FFQs led us to re-classify two food groups (grains and dairy products). Most DASH food components exhibited pronounced between-cohort variability, including non-full-fat dairy products (median intake ranging from 0.1 to 2.2 servings/day), sugar-sweetened beverages/sweets/added sugars (0.3–1.7 servings/day), fruits (1.1–3.1 servings/day), and vegetables (1.5–3.6 servings/day). We successfully developed a harmonized DASH score adapted to all cohorts being part of the ALPHABET consortium. This methodological work may benefit other research teams in adapting the DASH to their study’s specificities

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

Background: Type 2 diabetes (T2D) is a heterogeneous disease with well-known genetic and environmental risk factors contributing to its prevalence. Epigenetic mec

Maternal depression during pregnancy and cord blood DNA methylation: findings from the Avon Longitudinal Study of Parents and Children

Up to 13% of women may experience symptoms of depression during pregnancy or in the postpartum period. Depression during pregnancy has been associated with an increased risk of adverse neurodevelopmental outcomes in the child and epigenetic mechanisms could be one of the biological pathways to explain this association. In 844 mother–child pairs from the Avon Longitudinal Study of Parents and Children, we carried out an epigenome-wide association study (EWAS) to investigate associations between prospectively collected data on maternal depression ascertained by the Edinburgh Postnatal Depression Scale in pregnancy and DNA methylation in the cord blood of newborn offspring. In individual site analysis, we identified two CpG sites associated with maternal depression in the middle part of pregnancy. In our regional analysis, we identified 39 differentially methylated regions (DMRs). Seven DMRs were associated with depression at any time point during pregnancy, 7 associated with depression in mid-pregnancy, 23 were associated with depression in late pregnancy, and 2 DMRs were associated with depression throughout pregnancy. Several of these map to genes associated with psychiatric disease and brain development. We attempted replication in The Generation R Study and could not replicate our results. Although our findings in ALSPAC suggest that maternal depression could be associated with cord blood DNA methylation the results should be viewed as preliminary and hypothesis generating until further replicated in a larger sample

Associations of maternal dietary inflammatory potential and quality with offspring birth outcomes: An individual participant data pooled analysis of 7 European cohorts in the ALPHABET consortium

BACKGROUND: Adverse birth outcomes are major causes of morbidity and mortality during childhood and associate with a higher risk of noncommunicable diseases in adult life. Maternal periconception and antenatal nutrition, mostly focusing on single nutrients or foods, has been shown to influence infant birth o

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

Attention-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

Hypertensive Disorders of Pregnancy and DNA Methylation in Newborns Findings From the Pregnancy and Childhood Epigenetics Consortium

Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R2=0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development