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1.
Clin Epigenetics ; 13(1): 205, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-34784966

RESUMO

BACKGROUND: Hypertension and atherosclerosis may partly originate in early life. Altered epigenetic aging may be a mechanism underlying associations of early-life exposures and the development of cardiovascular risk factors in childhood. A discrepancy between chronological age and age predicted from neonatal DNA methylation data is referred to as age acceleration. It may either be positive, if DNA methylation age is older than clinical age, or negative, if DNA methylation age is younger than chronological age. We examined associations of age acceleration at birth ('gestational age acceleration'), and of age acceleration at school-age, with blood pressure and with intima-media thickness and distensibility of the common carotid artery, as markers of vascular structure and function, respectively, measured at age 10 years. RESULTS: This study was embedded in the Generation R Study, a population-based prospective cohort study. We included 1115 children with information on cord blood DNA methylation and blood pressure, carotid intima-media thickness or carotid distensibility. Gestational age acceleration was calculated using the Bohlin epigenetic clock, which was developed specifically for cord blood DNA methylation data. It predicts gestational age based on methylation levels of 96 CpGs from HumanMethylation450 BeadChip. We observed no associations of gestational age acceleration with blood pressure, carotid intima-media thickness or carotid distensibility at age 10 years. In analyses among children with peripheral blood DNA methylation measured at age 6 (n = 470) and 10 (n = 449) years, we also observed no associations of age acceleration at these ages with the same cardiovascular outcomes, using the 'skin and blood clock,' which predicts age based on methylation levels at 391 CpGs from HumanMethylation450 BeadChip. CONCLUSIONS: Our findings do not provide support for the hypothesis that altered epigenetic aging during the earliest phase of life is involved in the development of cardiovascular risk factors in childhood.

2.
Invest Ophthalmol Vis Sci ; 62(10): 16, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34406332

RESUMO

Purpose: To study the relatively high effect of the refractive error gene GJD2 in human myopia, and to assess its relationship with refractive error, ocular biometry and lifestyle in various age groups. Methods: The population-based Rotterdam Study (RS), high myopia case-control study MYopia STudy, and the birth-cohort study Generation R were included in this study. Spherical equivalent (SER), axial length (AL), axial length/corneal radius (AL/CR), vitreous depth (VD), and anterior chamber depth (ACD) were measured using standard ophthalmologic procedures. Biometric measurements were compared between GJD2 (rs524952) genotype groups; education and environmental risk score (ERS) were calculated to estimate gene-environment interaction effects, using the Synergy index (SI). Results: RS adults carrying two risk alleles had a lower SER and longer AL, ACD and VD (AA versus TT, 0.23D vs. 0.70D; 23.79 mm vs. 23.52 mm; 2.72 mm vs. 2.65 mm; 16.12 mm vs. 15.87 mm; all P < 0.001). Children carrying two risk alleles had larger AL/CR at ages 6 and 9 years (2.88 vs. 2.87 and 3.00 vs. 2.96; all P < 0.001). Education and ERS both negatively influenced myopia and the biometric outcomes, but gene-environment interactions did not reach statistical significance (SI 1.25 [95% confidence interval {CI}, 0.85-1.85] and 1.17 [95% CI, 0.55-2.50] in adults and children). Conclusions: The elongation of the eye caused by the GJD2 risk genotype follows a dose-response pattern already visible at the age of 6 years. These early effects are an example of how a common myopia gene may drive myopia.


Assuntos
Conexinas/genética , Regulação da Expressão Gênica , Miopia/genética , Vigilância da População , RNA/genética , Refração Ocular , Alelos , Câmara Anterior/diagnóstico por imagem , Comprimento Axial do Olho , Biometria , Estudos de Casos e Controles , Criança , Conexinas/biossíntese , Progressão da Doença , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Miopia/diagnóstico , Miopia/fisiopatologia , Estudos Prospectivos
3.
Pediatr Obes ; : e12844, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384140

RESUMO

BACKGROUND: Adaptations in maternal and foetal metabolic pathways may predispose to altered foetal growth and adverse birth outcomes. OBJECTIVE: To assess the associations of maternal early-pregnancy metabolite profiles and infant metabolite profiles at birth with foetal growth from first trimester onwards and the odds of adverse birth outcomes. METHODS: In a prospective population-based cohort among 976 Dutch pregnant women and their children, serum concentrations of amino acids, non-esterified fatty acids (NEFA), phospholipids (PL) and carnitines in maternal early-pregnancy blood and in cord blood were obtained by liquid-chromatography tandem mass spectrometry. Information on foetal growth was available from first trimester onwards. RESULTS: After false discovery rate correction for multiple testing, higher infant total and individual NEFA concentrations were associated with a lower weight, length, and head circumference at birth. Higher infant total and individual acyl-lysophosphatidylcholine (lyso.PC.a) and alkyl-lysophosphatidylcholine concentrations were associated with higher weight and head circumference (lyso.PC.a only) at birth, higher odds of LGA and lower odds of SGA. Few individual maternal metabolites were associated with foetal growth measures in third trimester and at birth, but not with the odds of adverse birth outcomes. CONCLUSIONS: Our results suggest that infant metabolite profiles, particularly total and individual lyso.PC.a and NEFA concentrations, were strongly related to growth measures at birth and the odds of adverse birth outcomes. Few individual maternal early-pregnancy metabolites, but not total metabolite concentrations, are associated with foetal growth measures in third trimester and at birth.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34390344

RESUMO

CONTEXT: Maternal prepregnancy BMI has a strong influence on gestational metabolism, but detailed metabolic alterations are unknown. OBJECTIVE: First, to examine the associations of maternal prepregnancy BMI with maternal early-pregnancy metabolite alterations. Second, to identify an early-pregnancy metabolite profile associated with birthweight in women with a higher prepregnancy BMI that improved prediction of birthweight compared to glucose and lipid concentrations. DESIGN, SETTING AND PARTICIPANTS: Prepregnancy BMI was obtained in a subgroup of 682 Dutch pregnant women from the Generation R prospective cohort study. MAIN OUTCOME MEASURES: Maternal non-fasting targeted amino acid, non-esterified fatty acid, phospholipid and carnitine concentrations measured in blood serum at mean gestational age of 12.8 weeks. Birthweight, obtained from medical records. RESULTS: A higher prepregnancy BMI was associated with 72 altered amino acid, non-esterified fatty acid, phospholipid and carnitine concentrations and 6 metabolite ratios reflecting Krebs cycle, inflammatory, oxidative stress and lipid metabolic processes (p-values<0.05). Using penalized regression models, a metabolite profile was selected including 15 metabolites and 4 metabolite ratios, based on its association with birthweight in addition to prepregnancy BMI. The adjusted R 2 of birthweight was 6.1% for prepregnancy BMI alone, 6.2% after addition of glucose and lipid concentrations and 12.9% after addition of the metabolite profile. CONCLUSIONS: A higher maternal prepregnancy BMI was associated with altered maternal early-pregnancy amino acids, non-esterified fatty acids, phospholipids and carnitines. Using these metabolites, we identified a maternal metabolite profile which improved prediction of birthweight in women with a higher prepregnancy BMI compared to glucose and lipid concentrations.

5.
Clin Nutr ; 40(9): 5133-5140, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34461587

RESUMO

BACKGROUND & AIMS: Suboptimal circulating vitamin B12, folate and homocysteine concentrations during fetal life seem to be associated with cardiometabolic health at school-age. We examined whether fetal exposure to lower circulating vitamin B12 and folate concentrations and higher circulating homocysteine concentrations is also associated with early signs of atherosclerosis at school-age. METHODS: This study among 3826 school-age children and their mothers was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onwards. We examined the associations of early-pregnancy and cord blood serum total and active B12 and plasma folate and homocysteine concentrations with common carotid artery intima-media thickness and distensibility in the children aged ten years. RESULTS: As compared to normal early-pregnancy serum total B12 concentrations (≥145 pmol/L), low serum total B12 concentrations (<145 pmol/L) were associated with higher carotid intima-media thickness in the children at school-age (difference 0.09 standard deviations score (SDS); 95% confidence interval (CI): 0.01, 0.16). As compared to normal early-pregnancy plasma folate concentrations (≥8 nmol/L), low plasma folate concentrations (<8 nmol/L) were associated with lower carotid distensibility in the children at school-age (difference -0.16 SDS; 95% CI: -0.28, -0.04). Early-pregnancy circulating total and active B12, folate and homocysteine concentrations measured continuously were not associated with carotid intima-media thickness or carotid distensibility in the children at school-age. One SDS higher plasma homocysteine concentrations measured in cord blood at birth was associated with a -0.05 SDS (95% CI: -0.09, -0.02) lower carotid distensibility at school-age. Cord blood total and active B12 and folate concentrations were not associated with carotid intima-media thickness or carotid distensibility at school-age. CONCLUSIONS: Circulating total B12, folate and homocysteine concentrations during fetal life seem to be associated with markers of subclinical atherosclerosis at school-age. Further studies need to examine the causality and mechanisms underlying these associations.

6.
Am J Med Genet B Neuropsychiatr Genet ; 186(4): 228-241, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34170065

RESUMO

Low prosocial behavior in childhood has been consistently linked to later psychopathology, with evidence supporting the influence of both genetic and environmental factors on its development. Although neonatal DNA methylation (DNAm) has been found to prospectively associate with a range of psychological traits in childhood, its potential role in prosocial development has yet to be investigated. This study investigated prospective associations between cord blood DNAm at birth and low prosocial behavior within and across four longitudinal birth cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. We examined (a) developmental trajectories of "chronic-low" versus "typical" prosocial behavior across childhood in a case-control design (N = 2,095), and (b) continuous "low prosocial" scores at comparable cross-cohort time-points (N = 2,121). Meta-analyses were performed to examine differentially methylated positions and regions. At the cohort-specific level, three CpGs were found to associate with chronic low prosocial behavior; however, none of these associations was replicated in another cohort. Meta-analysis revealed no epigenome-wide significant CpGs or regions. Overall, we found no evidence for associations between DNAm patterns at birth and low prosocial behavior across childhood. Findings highlight the importance of employing multi-cohort approaches to replicate epigenetic associations and reduce the risk of false positive discoveries.

7.
J Psychiatr Res ; 140: 214-220, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34118639

RESUMO

Psychiatric symptoms are interrelated and found to be largely captured by a general psychopathology factor (GPF). Although epigenetic mechanisms, such as DNA methylation (DNAm), have been linked to individual psychiatric outcomes, associations with GPF remain unclear. Using data from 440 children aged 10 years participating in the Generation R Study, we examined the associations of DNAm with both general and specific (internalizing, externalizing) factors of psychopathology. Genome-wide DNAm levels, measured in peripheral blood using the Illumina 450K array, were clustered into wider co-methylation networks ('modules') using a weighted gene co-expression network analysis. One co-methylated module associated with GPF after multiple testing correction, while none associated with the specific factors. This module comprised of 218 CpG probes, of which 198 mapped onto different genes. The CpG most strongly driving the association with GPF was annotated to FZD1, a gene that has been implicated in schizophrenia and wider neurological processes. Associations between the probes contained in the co-methylated module and GPF were supported in an independent sample of children from the Avon Longitudinal Study of Parents and Children (ALSPAC), as evidenced by significant correlations in effect sizes. These findings might contribute to improving our understanding of dynamic molecular processes underlying complex psychiatric phenotypes.


Assuntos
Metilação de DNA , Transtornos Mentais , Criança , Ilhas de CpG/genética , Epigênese Genética , Genoma , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Transtornos Mentais/genética
8.
Hepatology ; 74(4): 1902-1913, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34008183

RESUMO

BACKGROUND AND AIMS: Gestational diabetes seems to be associated with offspring NAFLD. We hypothesized that maternal glucose concentrations across the full range may have persistent effects on offspring liver fat accumulation. APPROACH AND RESULTS: In a multiethnic, population-based, prospective cohort study among 2,168 women and their offspring, maternal early-pregnancy glucose concentrations were measured at a median of 13.1 weeks' gestation (95% CI, 9.6-17.2). Liver fat fraction was measured at 10 years by MRI. NAFLD was defined as liver fat fraction ≥5.0%. We performed analyses among all mothers with different ethnic backgrounds and those of European ancestry only. The multiethnic group had a median maternal early-pregnancy glucose concentration of 4.3 mmol/L (interquartile range, 3.9-4.9) and a 2.8% (n = 60) prevalence of NAFLD. The models adjusted for child age and sex only showed that in the multiethnic group, higher maternal early-pregnancy glucose concentrations were associated with higher liver fat accumulation and higher odds of NAFLD, but these associations attenuated into nonsignificance after adjustment for potential confounders. Among mothers of European ancestry only, maternal early-pregnancy glucose concentrations were associated with increased odds of NAFLD (OR, 1.95; 95% CI, 1.32; 2.88, after adjustment for confounders) per 1-mmol/L increase in maternal early-pregnancy glucose concentration. These associations were not explained by maternal prepregnancy and childhood body mass index, visceral fat, and metabolic markers. CONCLUSIONS: In this study, maternal early-pregnancy glucose concentrations were only among mothers of European ancestry associated with offspring NAFLD. The associations of higher maternal early-pregnancy glucose concentrations with offspring NAFLD may differ between ethnic groups.

9.
J Clin Endocrinol Metab ; 106(9): e3400-e3413, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34050761

RESUMO

CONTEXT: Biological stress is related to cardiovascular disease in adults. The associations of stress with cardiovascular and metabolic diseases may originate in childhood. OBJECTIVE: This work aims to examine the associations of hair cortisol concentrations at age 6 years with cardiometabolic risk factors at ages 6 and 10 years. METHODS: Cortisol concentrations were measured in hair of 6-year-old children (n = 2598) participating in the Generation R Study, a population-based prospective cohort study in Rotterdam, the Netherlands. Main outcome measures included blood pressure, heart rate, concentrations of insulin, glucose, lipids, and C-reactive protein in blood at ages 6 and 10 years. RESULTS: Higher hair cortisol concentrations at age 6 years were associated with higher systolic blood pressure at age 10 years (difference 0.17 SD score; 95% CI, 0.03-0.31). The association attenuated into nonsignificance after adjustment for childhood body mass index (BMI) at age 6 years. Higher hair cortisol concentrations at age 6 years were associated with an increase in total and low-density lipoprotein cholesterol between ages 6 and 10 years but not with those measurements at age 6 or 10 years. Hair cortisol concentrations were not associated with other cardiometabolic risk factors at age 6 or 10 years. CONCLUSION: Hair cortisol concentrations were not independent of BMI associated with cardiometabolic risk factors at 6 or 10 years. The associations of biological stress with cardiometabolic risk factors may develop at later ages.


Assuntos
Fatores de Risco Cardiometabólico , Cabelo/química , Hidrocortisona/análise , Glicemia/análise , Pressão Sanguínea , Índice de Massa Corporal , Proteína C-Reativa/análise , Criança , Estudos de Coortes , Feminino , Frequência Cardíaca , Humanos , Insulina/sangue , Lipídeos/sangue , Masculino , Países Baixos/epidemiologia , Estudos Prospectivos , Fatores de Risco
10.
Clin Epigenetics ; 13(1): 95, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33926538

RESUMO

BACKGROUND: Circulating folate, vitamin B12 and homocysteine concentrations during fetal development have been associated with health outcomes in childhood. Changes in fetal DNA methylation may be an underlying mechanism. This may be reflected in altered epigenetic aging of the fetus, as compared to chronological aging. The difference between gestational age derived in clinical practice and gestational age predicted from neonatal DNA methylation data is referred to as gestational age acceleration. Differences in circulating folate, vitamin B12 and homocysteine concentrations during fetal development may be associated with gestational age acceleration. RESULTS: Up to 1346 newborns participating in the Generation R Study, a population-based prospective cohort study, had both cord blood DNA methylation data available and information on plasma folate, serum total and active B12 and plasma homocysteine concentrations, measured in early pregnancy and/or in cord blood. A subgroup of 380 newborns had mothers with optimal pregnancy dating based on a regular menstrual cycle and a known date of last menstrual period. For comparison, gestational age acceleration was calculated based the method of both Bohlin and Knight. In the total study population, which was more similar to Bohlin's training population, one standard deviation score (SDS) higher maternal plasma homocysteine concentrations was nominally associated with positive gestational age acceleration [0.07 weeks, 95% confidence interval (CI) 0.02, 0.13] by Bohlin's method. In the subgroup with pregnancy dating based on last menstrual period, the method that was also used in Knight's training population, one SDS higher cord serum total and active B12 concentrations were nominally associated with negative gestational age acceleration [(- 0.16 weeks, 95% CI - 0.30, - 0.02) and (- 0.15 weeks, 95% CI - 0.29, - 0.01), respectively] by Knight's method. CONCLUSIONS: We found some evidence to support associations of higher maternal plasma homocysteine concentrations with positive gestational age acceleration, suggesting faster epigenetic than clinical gestational aging. Cord serum vitamin B12 concentrations may be associated with negative gestational age acceleration, indicating slower epigenetic than clinical gestational aging. Future studies could examine whether altered fetal epigenetic aging underlies the associations of circulating homocysteine and vitamin B12 blood concentrations during fetal development with long-term health outcomes.

11.
Eur J Epidemiol ; 36(5): 565-580, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33884544

RESUMO

The Horizon2020 LifeCycle Project is a cross-cohort collaboration which brings together data from multiple birth cohorts from across Europe and Australia to facilitate studies on the influence of early-life exposures on later health outcomes. A major product of this collaboration has been the establishment of a FAIR (findable, accessible, interoperable and reusable) data resource known as the EU Child Cohort Network. Here we focus on the EU Child Cohort Network's core variables. These are a set of basic variables, derivable by the majority of participating cohorts and frequently used as covariates or exposures in lifecourse research. First, we describe the process by which the list of core variables was established. Second, we explain the protocol according to which these variables were harmonised in order to make them interoperable. Third, we describe the catalogue developed to ensure that the network's data are findable and reusable. Finally, we describe the core data, including the proportion of variables harmonised by each cohort and the number of children for whom harmonised core data are available. EU Child Cohort Network data will be analysed using a federated analysis platform, removing the need to physically transfer data and thus making the data more accessible to researchers. The network will add value to participating cohorts by increasing statistical power and exposure heterogeneity, as well as facilitating cross-cohort comparisons, cross-validation and replication. Our aim is to motivate other cohorts to join the network and encourage the use of the EU Child Cohort Network by the wider research community.


Assuntos
Bases de Dados Factuais/normas , Disseminação de Informação , Criança , Pré-Escolar , Estudos de Coortes , Europa (Continente) , Humanos , Saúde Pública
12.
J Nutr ; 151(6): 1628-1636, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33758913

RESUMO

BACKGROUND: Higher circulating folate and vitamin B-12 concentrations and lower circulating homocysteine concentrations during pregnancy seem to be associated with fetal development. These micronutrients may also be associated with cardiometabolic health. OBJECTIVE: We examined the associations of circulating folate, vitamin B-12, and homocysteine concentrations during pregnancy and in neonates with childhood cardiometabolic outcomes. METHODS: This study was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onward. We sampled blood in early pregnancy and cord blood. We measured cardiometabolic outcomes in the children at school age. Among 4449 children aged 10 y (median: 9.7; 95% range: 9.3, 10.7), we examined associations of plasma folate, serum vitamin B-12, and plasma homocysteine concentrations in early pregnancy and at birth with BMI, body fat distribution, heart rate, blood pressure, and insulin, glucose, and lipid concentrations, using linear regression models. Using logistic models, we examined the associations of these micronutrients with risks of overweight/obesity and clustering of cardiovascular risk factors. RESULTS: One standard deviation score (SDS) higher maternal plasma folate concentration was associated with lower BMI (-0.04 SDS; 95% CI: -0.08, -0.01), android-to-gynoid fat ratio (-0.04 SDS; 95% CI: -0.07, -0.01), systolic blood pressure (-0.06 SDS; 95% CI: -0.10, -0.03), risk of overweight (OR: 0.87; 95% CI: 0.78, 0.96), and clustering of cardiovascular risk factors (OR: 0.79; 95% CI: 0.68, 0.91). One SDS higher maternal serum total B-12 concentration was associated with lower glucose (-0.06 SDS; 95% CI: -0.10, -0.02) and higher HDL cholesterol concentrations (0.04 SDS; 95% CI: 0.00, 0.08). Cord blood folate, vitamin B-12, and homocysteine concentrations were not consistently associated with cardiometabolic outcomes. CONCLUSIONS: Subtle differences in circulating folate and vitamin B-12 concentrations in early pregnancy may be associated with child cardiometabolic health at age 10 y. The causality and mechanisms underlying these associations need further study.

13.
PLoS One ; 16(1): e0245475, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33476328

RESUMO

INTRODUCTION: Depression, cardiovascular diseases and diabetes are among the major non-communicable diseases, leading to significant disability and mortality worldwide. These diseases may share environmental and genetic determinants associated with multimorbid patterns. Stressful early-life events are among the primary factors associated with the development of mental and physical diseases. However, possible causative mechanisms linking early life stress (ELS) with psycho-cardio-metabolic (PCM) multi-morbidity are not well understood. This prevents a full understanding of causal pathways towards the shared risk of these diseases and the development of coordinated preventive and therapeutic interventions. METHODS AND ANALYSIS: This paper describes the study protocol for EarlyCause, a large-scale and inter-disciplinary research project funded by the European Union's Horizon 2020 research and innovation programme. The project takes advantage of human longitudinal birth cohort data, animal studies and cellular models to test the hypothesis of shared mechanisms and molecular pathways by which ELS shapes an individual's physical and mental health in adulthood. The study will research in detail how ELS converts into biological signals embedded simultaneously or sequentially in the brain, the cardiovascular and metabolic systems. The research will mainly focus on four biological processes including possible alterations of the epigenome, neuroendocrine system, inflammatome, and the gut microbiome. Life-course models will integrate the role of modifying factors as sex, socioeconomics, and lifestyle with the goal to better identify groups at risk as well as inform promising strategies to reverse the possible mechanisms and/or reduce the impact of ELS on multi-morbidity development in high-risk individuals. These strategies will help better manage the impact of multi-morbidity on human health and the associated risk.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Depressão/epidemiologia , Depressão/etiologia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Estresse Psicológico/complicações , Adulto , Experiências Adversas da Infância/psicologia , Biomarcadores/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/psicologia , Criança , Depressão/metabolismo , Depressão/psicologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/psicologia , Meio Ambiente , Humanos , Estudos Longitudinais , Morbidade , Fatores de Risco
14.
Mol Psychiatry ; 26(6): 2148-2162, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33420481

RESUMO

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10-7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.


Assuntos
Metilação de DNA , Epigenoma , Adolescente , Adulto , Idoso , Agressão , Criança , Pré-Escolar , Ilhas de CpG/genética , Metilação de DNA/genética , Epigênese Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Longevidade , Pessoa de Meia-Idade , Adulto Jovem
15.
Hum Mol Genet ; 30(1): 119-134, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33450751

RESUMO

DNA methylation (DNAm) is known to play a pivotal role in childhood health and development, but a comprehensive characterization of genome-wide DNAm trajectories across this age period is currently lacking. We have therefore performed a series of epigenome-wide association studies in 5019 blood samples collected at multiple time-points from birth to late adolescence from 2348 participants of two large independent cohorts. DNAm profiles of autosomal CpG sites (CpGs) were generated using the Illumina Infinium HumanMethylation450 BeadChip. Change over time was widespread, observed at over one-half (53%) of CpGs. In most cases, DNAm was decreasing (36% of CpGs). Inter-individual variation in linear trajectories was similarly widespread (27% of CpGs). Evidence for non-linear change and inter-individual variation in non-linear trajectories was somewhat less common (11 and 8% of CpGs, respectively). Very little inter-individual variation in change was explained by sex differences (0.4% of CpGs) even though sex-specific DNAm was observed at 5% of CpGs. DNAm trajectories were distributed non-randomly across the genome. For example, CpGs with decreasing DNAm were enriched in gene bodies and enhancers and were annotated to genes enriched in immune-developmental functions. In contrast, CpGs with increasing DNAm were enriched in promoter regions and annotated to genes enriched in neurodevelopmental functions. These findings depict a methylome undergoing widespread and often non-linear change throughout childhood. They support a developmental role for DNA methylation that extends beyond birth into late adolescence and has implications for understanding life-long health and disease. DNAm trajectories can be visualized at http://epidelta.mrcieu.ac.uk.


Assuntos
Metilação de DNA/genética , Epigênese Genética , Epigenoma/genética , Adolescente , Fatores Etários , Criança , Pré-Escolar , Ilhas de CpG/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Caracteres Sexuais
16.
Mol Psychiatry ; 26(6): 1832-1845, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33414500

RESUMO

Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.


Assuntos
Metilação de DNA , Epigenoma , Ansiedade/genética , Metilação de DNA/genética , Epigênese Genética/genética , Epigenômica , Feminino , Humanos , Gravidez
17.
Hepatology ; 73(2): 560-570, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33140427

RESUMO

BACKGROUND AND AIMS: Sugar-containing beverage intake is a major risk factor for obesity in both children and adults and appears to be associated with NAFLD in adults. The purpose of this study was to examine the associations between sugar-containing beverage intake in infancy and liver fat accumulation and NAFLD among school-aged children. APPROACH AND RESULTS: In a population-based prospective cohort study of 1,940 infants, we assessed sugar-containing beverage intake at 1 year with a validated Food Frequency Questionnaire. Liver fat fraction and NAFLD (liver fat fraction ≥5.0%) were assessed with MR. Higher sugar-containing beverage intake in infancy was not associated with higher liver fat accumulation at 10 years of age when assessed continuously (SD, 0.03; 95% CI, - 0.02, 0.07, per one-serving/day increase of sugar-containing beverage intake) or categorically (P = 0.38). However, compared to infants with <1.0 serving/day, those with >2.0 servings/day had the highest odds of NAFLD at 10 years of age (OR, 3.02; 95% CI, 1.34, 6.83). These associations remained borderline significant after additional adjustment for sugar-containing beverage intake and body mass index at school age (P = 0.13). Stratified analyses showed stronger associations between sugar-containing beverage intake in infancy and NAFLD at 10 years of age among children of mothers with lower educational attainment (OR, 1.48; 95% CI, 1.12, 1.97) and among children with overweight or obesity (OR, 1.47; 95% CI, 1.05, 2.07). CONCLUSIONS: Higher sugar-containing beverage intake in infancy was associated with NAFLD in school-aged children, independent of sugar-containing beverage intake and body mass index at school age. Limiting the intake of sugar-containing beverages in infancy may help prevent liver steatosis at school age.


Assuntos
Inquéritos sobre Dietas/estatística & dados numéricos , Fenômenos Fisiológicos da Nutrição do Lactente , Fígado/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Bebidas Adoçadas com Açúcar/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Fígado/patologia , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Estudos Prospectivos , Fatores de Risco
18.
J Clin Endocrinol Metab ; 106(2): e551-e561, 2021 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-33119748

RESUMO

CONTEXT: Stress may lead to an adverse body fat distribution from childhood onwards. OBJECTIVE: To examine the associations of hair cortisol concentration (HCC) at 6 years with general and organ fat measures, risk of overweight, and nonalcoholic fatty liver disease (NAFLD) at 10 years and to assess whether these were independent of adiposity measures at 6 years. DESIGN, SETTING AND PARTICIPANTS: HCCs were measured in hair of 6-year-old children (n = 2042) participating in the Generation R Study, a population-based prospective cohort study. MAIN OUTCOME MEASURES: Body mass index (BMI), fat mass index measured by dual-energy X-ray absorptiometry scan, and visceral fat index, pericardial fat index, liver fat fraction measured by magnetic resonance imaging and risk of overweight and NAFLD were obtained at 10 years. RESULTS: The associations of higher HCC at 6 years, with higher BMI, fat mass index, and increased risk of overweight at age 10 years are explained by the relationships observed at 6 years. HCCs at 6 years were associated with a higher liver fat fraction (difference 0.11 liver fat fraction standard deviation score; 95% confidence interval [CI] 0.03, 0.18) and a higher risk of NAFLD at 10 years (odds ratio 1.95; 95% CI 1.06, 3.56), independent of fat mass index at 6 years. HCCs were not associated with pericardial or visceral fat indices. CONCLUSIONS: Higher HCCs at 6 years were associated with higher BMI, fat mass index, liver fat fraction, and higher risks of overweight and NAFLD at 10 years. Only the associations for liver fat fraction and NAFLD were independent of fat mass index at 6 years.


Assuntos
Adiposidade/fisiologia , Cabelo/química , Hidrocortisona/análise , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Fatores Etários , Criança , Desenvolvimento Infantil/fisiologia , Pré-Escolar , Estudos de Coortes , Cortisona/análise , Cortisona/metabolismo , Feminino , Cabelo/metabolismo , Humanos , Hidrocortisona/metabolismo , Recém-Nascido , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Países Baixos/epidemiologia , Tamanho do Órgão , Sobrepeso/epidemiologia , Sobrepeso/etiologia , Sobrepeso/metabolismo , Obesidade Pediátrica/epidemiologia , Obesidade Pediátrica/etiologia , Obesidade Pediátrica/metabolismo , Gravidez , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/metabolismo , Complicações na Gravidez/psicologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fatores de Risco , Estresse Psicológico/complicações , Estresse Psicológico/epidemiologia , Estresse Psicológico/metabolismo
19.
J Dev Orig Health Dis ; 12(1): 113-123, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32327008

RESUMO

Epigenetic programming is essential for lineage differentiation, embryogenesis and placentation in early pregnancy. In epigenetic association studies, DNA methylation is often examined in DNA derived from white blood cells, although its validity to other tissues of interest remains questionable. Therefore, we investigated the tissue specificity of epigenome-wide DNA methylation in newborn and placental tissues. Umbilical cord white blood cells (UC-WBC, n = 25), umbilical cord blood mononuclear cells (UC-MNC, n = 10), human umbilical vein endothelial cells (HUVEC, n = 25) and placental tissue (n = 25) were obtained from 36 uncomplicated pregnancies. Genome-wide DNA methylation was measured by the Illumina HumanMethylation450K BeadChip. Using UC-WBC as a reference tissue, we identified 3595 HUVEC tissue-specific differentially methylated regions (tDMRs) and 11,938 placental tDMRs. Functional enrichment analysis showed that HUVEC and placental tDMRs were involved in embryogenesis, vascular development and regulation of gene expression. No tDMRs were identified in UC-MNC. In conclusion, the extensive amount of genome-wide HUVEC and placental tDMRs underlines the relevance of tissue-specific approaches in future epigenetic association studies, or the use of validated representative tissues for a certain disease of interest, if available. To this purpose, we herewith provide a relevant dataset of paired, tissue-specific, genome-wide methylation measurements in newborn tissues.

20.
Epigenetics ; : 1-13, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33331245

RESUMO

Altered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analyzed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 children and 1,962 adolescent whole-blood samples derived from 10 cohorts. DNA methylation was measured using Illumina Infinium Methylation 450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for the association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels.

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