Maternal Caffeine Intake and DNA Methylation in Newborn Cord Blood

Abstract Objectives Prior research has suggested that epigenetic mechanisms may underly associations between maternal caffeine intake and adverse childhood metabolic outcomes. We examined preconception and early pregnancy maternal caffeine exposure with DNA methylation (DNAm) patterns in the cord blood of 378 neonates. Methods DNAm was profiled by the Infinium MethylationEPIC BeadChip in women enrolled in the EAGeR Trial. Maternal serum was collected 1–2 cycles preconception and at 8 weeks gestation as was self-reported caffeinated beverage intake through standardized questionnaires or daily diaries. Serum caffeine, paraxanthine, and theobromine were measured by liquid chromatography mass spectrometry. We performed multivariable robust linear regression to assess associations between maternal caffeine and methylation β-values and Ingenuity Pathway Analysis to evaluate biologic implications. Results Preconceptionally, 65%, 21% and 7% reported any soda, coffee or tea intake, respectively with the majority consuming on average ≤ 1 serving/day. Preconception self-reported intake compared to no intake was associated with DNAm at cg09002832 near GLIS3 (false discovery rate [FDR] p = 0.036). No associations with self-reported intake were found during pregnancy. Preconception serum markers were not associated with individual CpG sites (FDR > 5%), though pregnancy theobromine (tertile 2 vs 1) was associated with DNAm at cg09460369 near RAB2A (FDR p = 0.012). Overlapping pathways for the top 100 CpG sites identified in the preconception intake and pregnancy theobromine analyses elucidated cell cycle and lipid metabolism processes. Conclusions Few differences in DNAm were identified in association with maternal caffeine intake in this low consumption population. DNAm changes from preconception caffeine or pregnancy theobromine exposure may be linked to signaling networks involving lipid metabolism, but further research among women with higher caffeine and theobromine exposure is warranted. Funding Sources Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

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Birthweight DNA methylation signatures in infant saliva

Clinical Epigenetics ◽

10.1186/s13148-021-01053-1 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Chiara Moccia ◽

Maja Popovic ◽

Elena Isaevska ◽

Valentina Fiano ◽

Morena Trevisan ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Gestational Age ◽

Low Birthweight ◽

Continuous Variable ◽

Linear Regression Models ◽

Association Analyses ◽

Cpg Sites ◽

Adverse Health Outcomes ◽

The Look

Abstract Background Low birthweight has been repeatedly associated with long-term adverse health outcomes and many non-communicable diseases. Our aim was to look-up cord blood birthweight-associated CpG sites identified by the PACE Consortium in infant saliva, and to explore saliva-specific DNA methylation signatures of birthweight. Methods DNA methylation was assessed using Infinium HumanMethylation450K array in 135 saliva samples collected from children of the NINFEA birth cohort at an average age of 10.8 (range 7–17) months. The association analyses between birthweight and DNA methylation variations were carried out using robust linear regression models both in the exploratory EWAS analyses and in the look-up of the PACE findings in infant saliva. Results None of the cord blood birthweight-associated CpGs identified by the PACE Consortium was associated with birthweight when analysed in infant saliva. In saliva EWAS analyses, considering a false discovery rate p-values < 0.05, birthweight as continuous variable was associated with DNA methylation in 44 CpG sites; being born small for gestational age (SGA, lower 10th percentile of birthweight for gestational age according to WHO reference charts) was associated with DNA methylation in 44 CpGs, with only one overlapping CpG between the two analyses. Despite no overlap with PACE results at the CpG level, two of the top saliva birthweight CpGs mapped at genes associated with birthweight with the same direction of the effect also in the PACE Consortium (MACROD1 and RPTOR). Conclusion Our study provides an indication of the birthweight and SGA epigenetic salivary signatures in children around 10 months of age. DNA methylation signatures in cord blood may not be comparable with saliva DNA methylation signatures at about 10 months of age, suggesting that the birthweight epigenetic marks are likely time and tissue specific.

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DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures

Clinical Epigenetics ◽

10.1186/s13148-020-00957-8 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Monica del C. Gomez-Alonso ◽

Anja Kretschmer ◽

Rory Wilson ◽

Liliane Pfeiffer ◽

Ville Karhunen ◽

...

Keyword(s):

Dna Methylation ◽

Lipid Metabolism ◽

Population Based ◽

Total Serum ◽

Resonance Spectroscopy ◽

Metabolic Disturbances ◽

Cpg Sites ◽

Gene Transcripts

Abstract Background The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances. Results We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10−10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations. Conclusion Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.

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DNA methylation patterns of β-globin cluster in β-thalassemia patients

Clinical Epigenetics ◽

10.1186/s13148-020-00987-2 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Xiuqin Bao ◽

Yangjin Zuo ◽

Diyu Chen ◽

Cunyou Zhao

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Methylation Level ◽

Epigenetic Modification ◽

Fetal Hemoglobin ◽

Cpg Sites ◽

Hbf Level ◽

Globin Promoter ◽

Methylation Patterns ◽

Normal Controls

Abstract Background Reactivation of fetal hemoglobin (HbF, α2γ2) holds a therapeutic target for β-thalassemia and sickle cell disease. Although many HbF regulators have been identified, the methylation patterns in β-globin cluster driving the fetal-to-adult hemoglobin switch remains to be determined. Results Here, we evaluated DNA methylation patterns of the β-globin cluster from peripheral bloods of 105 β0/β0 thalassemia patients and 44 normal controls. We also recruited 15 bone marrows and 4 cord blood samples for further evaluation. We identified that the CpG sites in the locus control region (LCR) DNase I hypersensitive site 4 and 3 (HS4-3) regions, and γ- and β-globin promoters displayed hypomethylation in β0/β0-thalassemia patients, especially for the patients with high HbF level, as compared with normal controls. Furthermore, hypomethylations in most of CpG sites of the HS4-3 core regions were also observed in bone marrows (BM) of β0/β0-patients compared with normal controls; and methylation level of γ-globin promoter -50 and + 17 CpG sites showed lower methylation level in patients with high HbF level compared with those with low HbF level and a negative correlation with HbF level among β0-thalassemia patients. Finally, γ-globin promoter + 17 and + 50 CpG sites also displayed significant hypomethylation in cord blood (CB) tissues compared with BM tissues from normal controls. Conclusions Our findings revealed methylation patterns in β-globin cluster associated with β0 thalassemia disease and γ-globin expression, contributed to understand the epigenetic modification in β0 thalassemia patients and provided candidate targets for the therapies of β-hemoglobinopathies.

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Arsenic exposure in early pregnancy alters genome-wide DNA methylation in cord blood, particularly in boys

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174414000221 ◽

2014 ◽

Vol 5 (4) ◽

pp. 288-298 ◽

Cited By ~ 91

Author(s):

K. Broberg ◽

S. Ahmed ◽

K. Engström ◽

M. B. Hossain ◽

S. Jurkovic Mlakar ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Mononuclear Cells ◽

De Novo ◽

Arsenic Exposure ◽

Later Life ◽

Linear Regression Models ◽

Early Gestation ◽

Cpg Sites ◽

Genome Wide

Early-life inorganic arsenic exposure influences not only child health and development but also health in later life. The adverse effects of arsenic may be mediated by epigenetic mechanisms, as there are indications that arsenic causes altered DNA methylation of cancer-related genes. The objective was to assess effects of arsenic on genome-wide DNA methylation in newborns. We studied 127 mothers and cord blood of their infants. Arsenic exposure in early and late pregnancy was assessed by concentrations of arsenic metabolites in maternal urine, measured by high performance liquid chromatography-inductively coupled plasma mass spectrometry. Genome-wide 5-methylcytosine methylation in mononuclear cells from cord blood was analyzed by Infinium HumanMethylation450K BeadChip. Urinary arsenic in early gestation was associated with cord blood DNA methylation (Kolmogorov–Smirnov test, P-value<10–15), with more pronounced effects in boys than in girls. In boys, 372 (74%) of the 500 top CpG sites showed lower methylation with increasing arsenic exposure (rS-values>−0.62), but in girls only 207 (41%) showed inverse correlation (rS-values>−0.54). Three CpG sites in boys (cg15255455, cg13659051 and cg17646418), but none in girls, were significantly correlated with arsenic after adjustment for multiple comparisons. The associations between arsenic and DNA methylation were robust in multivariable-adjusted linear regression models. Much weaker associations were observed with arsenic exposure in late compared with early gestation. Pathway analysis showed overrepresentation of affected cancer-related genes in boys, but not in girls. In conclusion, early prenatal arsenic exposure appears to decrease DNA methylation in boys. Associations between early exposure and DNA methylation might reflect interference with de novo DNA methylation.

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DHA-rich n-3 PUFAs intake from the early- and mid-pregnancy decreases the weight gain by affecting the DNA methylation status among Chinese Han infants

Food & Nutrition Research ◽

10.29219/fnr.v65.7548 ◽

2021 ◽

Author(s):

Ping Li ◽

Xiaoyu Chen ◽

Tianyi Teng ◽

Xiuqin Fan ◽

Tiantian Tang ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Methylation Status ◽

Z Score ◽

Chinese Han ◽

Follow Up Study ◽

Cpg Sites

Background: Maternal exogenous docosahexaenoic acid (DHA)-rich n-3 polyunsaturated fatty acids (PUFAs) intake during the pregnancy, especially DHA, has inconsistent effects on reducing the fat storage of the infants in different clinical studies. Objectives: We sought to determine the effects of maternal exogenous DHA-rich n-3 PUFAs capsule intake from the different pregnancy periods on the weight gain of their infants through modifying the DNA methylation status of obesity-associated genes in the umbilical cord blood. Design: A prospective 3-year follow-up study after the pregnancy was enrolled in this cohort from May to October 2016. They were divided into different groups according to the initial time of exogenous DHA capsule intake through the questionnaires (S1 – early trimester, S2 – mid-trimester, S3 – late trimester, and control – without). The concentrations and compositions of DHA were determined by gas chromatography. We applied quantitative DNA methylation states of the obesity-associated genes in the umbilical cord blood. The growth outcomes and relevant Z-scores were recorded at birth and 1 and 2 years. The correlations between DNA methylation status of the obesity-associated genes with the consents of DNA and body mass index (BMI) values were investigated as the measures. Results: In total, 205 pregnant women and their infants were eligible for this follow-up study. The concentrations and compositions of DHA in the colostrum and umbilical cord blood were higher in the S1 and S2 groups than those in the control and S3 groups as well as the decreased weight, BMI, weight for age Z-score (WAZ) and BMI for age Z-score (BMI Z) at birth and 1 and/or 2 years, and higher levels of global DNA methylation and many CpG sites in the obesity-associated genes, such as CpG2, CpG9, CpG11, and CpG16 of PPAR-γ; CpG2,3, CpG4-6, CpG8, CpG9,10, CpG11, CpG15,16, and average of CCAAT/enhancer binding protein α (C/EBP-α); CpG1 and average of adiponectin; CpG1, CpG2, CpG3, CpG5, CpG6, CpG7, and average of insulin-like growth factor 2 (IGF-2); CpG6, CpG7, CpG9, CpG16, CpG23, and CpG24 of leptin, which were more obvious in the S1 group when compared with those in the S2 group. These above hypermethylation levels of CpG sites were negatively correlated with the BMI and positively related with the changes of DHA in the colostrum and umbilical cord blood. Conclusions: Maternal exogenous DHA-rich n-3 PUFAs intake from early- and mid- trimesters of the pregnancy may avoid the development of obesity among Chinese Han infants until 2 years by modulating DNA methylation states of obesity-associated genes, which could provide attractive targets for prenatal prevention of the metabolic disorders.

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Epigenome-wide contributions to individual differences in childhood phenotypes: A GREML approach

10.1101/2021.06.24.21259449 ◽

2021 ◽

Author(s):

Alexander Neumann ◽

Jean-Baptiste Pingault ◽

Janine F. Felix ◽

Vincent W. V. Jaddoe ◽

Henning Tiemeier ◽

...

Keyword(s):

Dna Methylation ◽

Birth Weight ◽

Cord Blood ◽

Gestational Age ◽

Cross Validation ◽

Epigenetic Mechanism ◽

School Age ◽

Adhd Symptoms ◽

Cpg Sites ◽

Variance Explained

Background: DNA methylation is an epigenetic mechanism involved in human development. Numerous epigenome-wide association studies (EWAS) have investigated the associations of DNA methylation at single CpG sites with childhood outcomes. However, the overall contribution of DNA methylation across the genome (R2Methylation) towards childhood phenotypes is unknown. An estimate of R2Methylation would provide context regarding the importance of DNA methylation explaining variance in health outcomes. Methods: We estimated the variance explained by epigenome-wide cord blood methylation (R2Methylation) for five childhood phenotypes: gestational age, birth weight, and body mass index (BMI), IQ and ADHD symptoms at school age. We adapted a genome-based restricted maximum likelihood (GREML) approach with cross-validation (CV) to DNA methylation data and applied it in two population-based birth cohorts: ALSPAC (n=775) and Generation R (n=1382). Results: Using information from >470,000 autosomal probes we estimated that DNA methylation at birth explains 45% (SDCV = 0.07) of gestational age variance and 16% (SDCV = 0.05) of birth weight variance. The R2Methylation estimates for BMI, IQ and ADHD symptoms at school age estimates were near 0% across almost all cross-validation iterations. Conclusions: The results suggest that cord blood methylation explains a moderate to large degree of variance in gestational age and birth weight, in line with the success of previous EWAS in identifying numerous CpG sites associated with these phenotypes. In contrast, we could not obtain a reliable estimate for school-age BMI, IQ and ADHD symptoms. This may reflect a null bias due to insufficient sample size to detect variance explained in more weakly associated phenotypes, although the true R2Methylation for these phenotypes is likely below that of gestational age and birth weight when using DNA methylation at birth.

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Trimester-Specific Associations of Prenatal Lead Exposure With Infant Cord Blood DNA Methylation at Birth

Epigenetics Insights ◽

10.1177/2516865720938669 ◽

2020 ◽

Vol 13 ◽

pp. 251686572093866 ◽

Cited By ~ 1

Author(s):

Christine A Rygiel ◽

Dana C Dolinoy ◽

Wei Perng ◽

Tamara R Jones ◽

Maritsa Solano ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Differential Methylation ◽

P Value ◽

Environmental Toxicants ◽

Linear Regression Models ◽

Birth Cohorts ◽

Tibia Bone ◽

Cpg Sites ◽

Pb Exposure

Gestational exposure to lead (Pb) adversely impacts offspring health through multiple mechanisms, one of which is the alteration of the epigenome including DNA methylation. This study aims to identify differentially methylated CpG sites associated with trimester-specific maternal Pb exposure in umbilical cord blood (UCB) leukocytes. Eighty-nine mother-child dyads from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) longitudinal birth cohorts with available UCB samples were selected for DNA methylation analysis via the Infinium Methylation EPIC BeadChip, which quantifies methylation at >850 000 CpG sites. Maternal blood lead levels (BLLs) during each trimester (T1: 6.56 ± 5.35 µg/dL; T2: 5.93 ± 5.00 µg/dL; T3: 6.09 ± 4.51 µg/dL), bone Pb (patella: 11.8 ± 9.25 µg/g; tibia: 11.8 ± 6.73 µg/g), a measure of cumulative Pb exposure, and UCB Pb (4.86 ± 3.74 µg/dL) were measured. After quality control screening, data from 786 024 CpG sites were used to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) by Pb biomarkers using separate linear regression models, controlling for sex and estimated UCB cell-type proportions. We identified 3 DMPs associated with maternal T1 BLL, 2 with T3 BLL, and 2 with tibia bone Pb. We identified one DMR within PDGFRL associated with T1 BLL, one located at chr6:30095136-30095295 with T3 BLL, and one within TRHR with tibia bone Pb (adjusted P-value < .05). Pathway analysis identified 15 overrepresented gene pathways for differential methylation that overlapped among all 3 trimesters with the largest overlap between T1 and T2 (adjusted P-value < .05). Pathways of interest include nodal signaling pathway and neurological system processes. These data provide evidence for differential methylation by prenatal Pb exposure that may be trimester-specific.

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Socioeconomic status and DNA methylation from birth through mid-childhood: a prospective study in Project Viva

Epigenomics ◽

10.2217/epi-2019-0040 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1413-1427 ◽

Cited By ~ 2

Author(s):

Zachary M Laubach ◽

Wei Perng ◽

Andres Cardenas ◽

Sheryl L Rifas-Shiman ◽

Emily Oken ◽

...

Keyword(s):

Dna Methylation ◽

Socioeconomic Status ◽

Cord Blood ◽

Cpg Sites ◽

Infinium Humanmethylation450 Beadchip ◽

Genome Wide ◽

Peripheral Leukocytes ◽

A Prospective Study ◽

The Relationship ◽

Neighborhood Level

Aim: We investigated associations of prenatal socioeconomic status (SES) with DNA methylation at birth, and to explore persistence of associations into early (∼3 years) and mid-childhood (∼7 years) among 609 mother–child pairs in a Boston-area prebirth cohort. Materials & methods: First, we created a prenatal SES index comprising individual- and neighborhood-level metrics and examined associations of low (lowest 10%) versus high (upper 90%) SES with genome-wide DNA methylation in cord blood via the Infinium HumanMethylation450 BeadChip. Next, we evaluated persistence of associations detected in cord blood with DNA methylation of the same CpG sites measured in peripheral leukocytes in early- and mid-childhood. Results & conclusion: Low prenatal SES was associated with methylation at CpG sites near ACSF3, TNRC6C-AS1, MTMR4 and LRRN4. The relationship with LRRN4 persisted into early childhood.

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DNA Methylation at Birth is Associated with Childhood Serum Immunoglobulin E Levels

Epigenetics Insights ◽

10.1177/25168657211008108 ◽

2021 ◽

Vol 14 ◽

pp. 251686572110081

Author(s):

Luhang Han ◽

Akhilesh Kaushal ◽

Hongmei Zhang ◽

Latha Kadalayil ◽

Jiasong Duan ◽

...

Keyword(s):

Dna Methylation ◽

Gene Ontology ◽

Cord Blood ◽

Early Life ◽

Immunoglobulin E ◽

Allergic Diseases ◽

Total Serum ◽

Gene Ontology Analysis ◽

Serum Ige ◽

Cpg Sites

Immunoglobulin E (IgE) is known to play an important role in allergic diseases. Epigenetic traits acquired due to modification of deoxyribonucleic acid (DNA) methylation (DNAm) in early life may have phenotypic consequences through their role in transcriptional regulation with relevance to the developmental origins of diseases including allergy. However, epigenome-scale studies on the longitudinal association of cord blood DNAm with IgE over time are lacking. Our study aimed to examine the association of DNAm at birth with childhood serum IgE levels during early life. Genome-scale DNAm and total serum IgE measured at birth, 5, 8, and 11 years of children in the Taiwan Maternal and Infant Cohort Study were included in the study in the discovery stage. Linear mixed models were implemented to assess the association between cord blood DNAm at ~310K 5′-cytosine-phosphate-guanine-3′ (CpG) sites with repeated IgE measurements, adjusting for cord blood IgE. Identified statistically significant CpGs (at a false discovery rate, FDR, of 0.05) were further tested in an independent replication cohort, the Isle of Wight (IoW) birth cohort. We mapped replicated CpGs to genes and conducted gene ontology analysis using ToppFun to identify significantly enriched pathways and biological processes of the genes. Cord blood DNAm of 273 CpG sites were significantly (FDR = 0.05) associated with IgE levels longitudinally. Among the identified CpGs available in both cohorts (184 CpGs), 92 CpGs (50%) were replicated in the IoW in terms of consistency in direction of associations between DNA methylation and IgE levels later in life, and 16 of the 92 CpGs showed statistically significant associations ( P < .05). Gene ontology analysis identified 4 pathways (FDR = 0.05). The identified 16 CpG sites had the potential to serve as epigenetic markers associated with later IgE production, beneficial to allergic disease prevention and intervention.

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Association of Assisted Reproductive Technologies with offspring cord blood DNA methylation across cohorts

10.1101/2020.06.18.20134940 ◽

2020 ◽

Author(s):

Doretta Caramaschi ◽

James Jungius ◽

Christian M. Page ◽

Boris Novakovic ◽

Richard Saffery ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Study Design ◽

Assisted Reproductive Technologies ◽

Biological Effects ◽

Meta Analysis ◽

Reproductive Technologies ◽

P Value ◽

Cpg Sites

AbstractStudy questionIs DNA methylation at birth associated with having been conceived by assisted reproductive technologies (ART)?Summary answerThis study shows does not provide strong evidence of an association of conception by ART with variation in infant blood cell DNA methylation.What is known alreadyAssisted reproductive technologies (ART) are procedures used to help infertile/subfertile couples conceive. Due to its importance in gene regulation during early development programming, DNA methylation and its perturbations associated with ART could reveal new insights into the biological effects of ART and potential adverse offspring outcomes.Study designWe investigated the association of DNA methylation and ART using a case-control study design (N=205 ART cases and N=2439 non-ART controls in discovery cohorts; N=149 ART cases and N=58 non-ART controls in replication cohort).Participants/materials, settings, methodWe assessed the association between ART and DNA methylation at birth in cord blood (205 ART conceptions and 2439 naturally conceived controls) at >450000 CpG sites across the genome in two sub-samples of the UK Avon Longitudinal Study of Parents and Children (ALSPAC) and two sub-samples of the Norwegian Mother, Father and Child Cohort Study (MoBa) by meta-analysis. We explored replication of findings in the Australian Clinical review of the Health of adults conceived following Assisted Reproductive Technologies (CHART) study (N=149 ART conceptions and N=58 controls).Main results and the role of chanceThe ALSPAC and MoBa meta-analysis revealed evidence of association between conception by ART and DNA methylation (false-discovery-rate-corrected p-value < 0.05) at 5 CpG sites which are annotated to 2 genes. Methylation at 3 of these sites has been previously linked to cancer, aging, HIV infection and neurological diseases. None of these associations replicated in the CHART cohort. There was evidence of a functional role of ART-induced hypermethylation at CpG sites located within regulatory regions as shown by putative transcription factor binding and chromatin remodelling.Limitations, reasons for cautionsWhile insufficient power is likely, heterogeneity in types of ART and between populations may also contribute. Larger studies might identify replicable variation in DNA methylation at birth due to ART.Wider implications of the findingsART-conceived newborns present with divergent DNA methylation in cord blood white cells. If these associations are true and causal, they might have long-term consequences for offspring health.

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