Systematic identification of genetic influences on methylation across the human life course

BACKGROUND: The influence of genetic variation on complex diseases is potentially mediated through a range of highly dynamic epigenetic processes exhibiting temporal variation during development and later life. Here we present a catalogue of the genetic influences on DNA methylation (methylation quantitative trait loci (mQTL)) at five different life stages in human blood: children at birth, childhood, adolescence and their mothers during pregnancy and middle age. RESULTS: We show that genetic effects on methylation are highly stable across the life course and that developmental change in the genetic contribution to variation in methylation occurs primarily through increases in environmental or stochastic effects. Though we map a large proportion of the cis-acting genetic variation, a much larger component of genetic effects influencing methylation are acting in trans. However, only 7 % of discovered mQTL are trans-effects, suggesting that the trans component is highly polygenic. Finally, we estimate the contribution of mQTL to variation in complex traits and infer that methylation may have a causal role consistent with an infinitesimal model in which many methylation sites each have a small influence, amounting to a large overall contribution. CONCLUSIONS: DNA methylation contains a significant heritable component that remains consistent across the lifespan. Our results suggest that the genetic component of methylation may have a causal role in complex traits. The database of mQTL presented here provide a rich resource for those interested in investigating the role of methylation in disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-016-0926-z) contains supplementary material, which is available to authorized users

DNA methylation and body mass index:investigating identified methylation sites at HIF3A in a causal framework

Multiple differentially methylated sites and regions associated with adiposity have now been identified in large-scale cross-sectional studies. We tested for replication of associations between previously identified CpG sites at HIF3A and adiposity in ∼1,000 mother-offspring pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC). Availability of methylation and adiposity measures at multiple time points, as well as genetic data, allowed us to assess the temporal associations between adiposity and methylation and to make inferences regarding causality and directionality. Overall, our results were discordant with those expected if HIF3A methylation has a causal effect on BMI and provided more evidence for causality in the reverse direction (i.e., an effect of BMI on HIF3A methylation). These results are based on robust evidence from longitudinal analyses and were also partially supported by Mendelian randomization analysis, although this latter analysis was underpowered to detect a causal effect of BMI on HIF3A methylation. Our results also highlight an apparent long-lasting intergenerational influence of maternal BMI on offspring methylation at this locus, which may confound associations between own adiposity and HIF3A methylation. Further work is required to replicate and uncover the mechanisms underlying the direct and intergenerational effect of adiposity on DNA methylation.Rebecca C. Richmond, Gemma C. Sharp, Mary E. Ward, Abigail Fraser, Oliver Lyttleton, Wendy L. McArdle, Susan M. Ring, Tom R. Gaunt, Debbie A. Lawlor, George Davey Smith, and Caroline L. Relto

The epigenetic clock and physical development during childhood and adolescence:longitudinal analysis from a UK birth cohort

Additional file 4: S7. Pairwise genetic distance matrix for Cytochrome c oxidase subunit 1 (COI)

Prenatal and early life influences on epigenetic age in children:a study of mother-offspring pairs from two cohort studies

DNA methylation-based biomarkers of aging are highly correlated with actual age. Departures of methylation-estimated age from actual age can be used to define epigenetic measures of child development or age acceleration (AA) in adults. Very little is known about genetic or environmental determinants of these epigenetic measures of aging. We obtained DNA methylation profiles using Infinium HumanMethylation450 BeadChips across five time-points in 1018 mother-child pairs from the Avon Longitudinal Study of Parents and Children. Using the Horvath age estimation method, we calculated epigenetic age for these samples. AA was defined as the residuals from regressing epigenetic age on actual age. AA was tested for associations with cross-sectional clinical variables in children. We identified associations between AA and sex, birth weight, birth by caesarean section and several maternal characteristics in pregnancy, namely smoking, weight, BMI, selenium and cholesterol level. Offspring of non-drinkers had higher AA on average but this difference appeared to resolve during childhood. The associations between sex, birth weight and AA found in ARIES were replicated in an independent cohort (GOYA). In children, epigenetic AA measures are associated with several clinically relevant variables, and early life exposures appear to be associated with changes in AA during adolescence. Further research into epigenetic aging, including the use of causal inference methods, is required to better our understanding of aging

Epifania, recriação e ressentimento: fragmentos narrativos sobre a experiência da viagem na imigração italiana no Brasil

L'expérience du voyage dans le processus de l'immigration marque le premier contact avec l'inconnu. L'aventure de la traversée de l'océan signifie par conséquent l'abandon du seul monde tangible. Le nouveau monde va se dévoiler à l'émigrant au fur et à mesure que le navire avance en mer, en un mélange de représentations produites avant le départ et de nouvelles “idées-images” que l'expérience elle-même du voyage contribue à élaborer en continu. Au cours de ce processus, la lecture de "Sull'Oceano" d’Edmondo De Amicis permet une immersion dans ce monde fragmentaire d'images et des récits que l'émigrant va produire. Il tente par ce biais de comprendre sa propre expérience et son existence, en un monde entrecroisé de différentes expressions de la sensibilité. Lê nouveau monde se révèle, souvenir tout à la fois d’une terre que l’on a abandonnée et recréation d'une représentation pacificatrice

Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: Findings from the Avon Longitudinal Study of Parents and Children (ALSPAC)

© The Author 2014. Maternal smoking during pregnancy has been found to influence newborn DNA methylation in genes involved in fundamental developmental processes. It is pertinent to understand the degree to which the offspring methylomeis sensitive to the intensity and duration of prenatal smoking. An investigation of the persistence of offspring methylation associated with maternal smoking and the relative roles of the intrauterine and postnatal environment is alsowarranted. In the Avon Longitudinal Study of Parents and Children, we investigated associations between prenatal exposure to maternal smoking and offspring DNA methylation at multiple time points in approximately 800 mother-offspring pairs. In cord blood, methylation at 15 CpG sites in seven gene regions (AHRR, MYO1G, GFI1, CYP1A1, CNTNAP2, KLF13 and ATP9A) was associated with maternal smoking, and a dose-dependent response was observed in relation to smoking duration and intensity. Longitudinal analysis of blood DNA methylation in serial samples at birth, age 7 and 17 years demonstrated that some CpG sites showed reversibility of methylation (GFI1, KLF13 and ATP9A), whereas others showed persistently perturbed patterns (AHRR, MYO1G, CYP1A1 and CNTNAP2). Of those showing persistence, we explored the effect of postnatal smoke exposure and found that the major contribution to altered methylation was attributed to a critical window of in utero exposure. A comparison of paternal and maternal smoking and offspring methylation showed consistently stronger maternal associations, providing further evidence for causal intrauterine mechanisms. These findings emphasize the sensitivity of the methylome to maternal smoking during early development and the long-term impact of such exposure

Longitudinal analysis of DNA methylation associated with birth weight and gestational age

Gestational age (GA) and birth weight have been implicated in the determination of long-term health. It has been hypothesized that changes in DNAmethylationmaymediate these long-term effects.We obtainedDNAmethylation profiles from cord blood and peripheral blood at ages 7 and 17 in the same children from theAvon Longitudinal Studyof Parents andChildren. Repeated-measures data were used to investigate changes in birth-related methylation during childhood and adolescence. Ten developmental phenotypes (e.g. height) were analysed to identify possible mediation of health effects by DNAmethylation. In cord blood, methylation at 224 CpG sites was found to be associated with GA and 23 CpG sites with birth weight. Methylation changed in themajority of these sites over time, but neither birth characteristicwas strongly associatedwithmethylation at age 7 or 17 (using a conservative correction formultiple testing of P < 1.03 × 10–7), suggesting resolution of differentialmethylation by early childhood. Associations were observed between birth weight-associated CpG sites and phenotypic characteristics in childhood. One strong association involved birthweight,methylation of a CpG site proximal to theNFIX locus and bonemineral density at age 17. Analysis of serial methylation from birth to adolescence provided evidence for a lack of persistence of methylation differences beyond early childhood. Sites associated with birth weight were linked to developmental genes and have methylation levels which are associated with developmental phenotypes. Replication and interrogation of causal relationships are needed to substantiate whether methylation differences at birth influence the association between birth weight and development