Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium

Epigenetics refers to mitotically heritable changes to the DNA, which do not affect the DNA sequence, but can influence its function. Currently, DNA methylation is the most studied epigenetic phenomenon in large populations. It entails the binding of a methyl group, mainly to positions in genomic DNA where a cytosine is located next to a guanine, a cytosine-phosphate-guanine (CpG) site (Figure 1). DNA methylation at CpG sites can influence gene expression by altering the DNA’s three-dimensional structure and interacting with methyl-binding proteins, consequently affecting the binding of the gene transcription and chromatin-modifying machinery. There are approximately 28 million CpG sites in the human genome. DNA methylation is a dynamic process that can be influenced by genetic factors, as well as by environmental factors such as diet, air pollution, toxicants or smoking.1–4 Hence, DNA methylation may be seen as linking the genome to the environment with respect to health and disease. Early development is a period of profound changes in DNA methylation and may, as such, be a critical period for environmentally-induced DNA methylation changes.4 Hence, this period is of specific interest for DNA methylation studies in relation to specific exposures and long-term health outcomes.1,4–6 Schematic representation of DNA methylation. The figure shows a double DNA strand on the top right, with CpG sites which are methylated by the addition of a methyl group (M). DNA is transcribed into messenger RNA (mRNA). DNA methylation can influence transcription either positively or negatively, depending on the location of the methylated site. After transcription, mRNA is translated into proteins. Adapted with permission from Felix JF et al.64 DNA methylation modifications in early life represent an important potential mechanism for studies on the developmental origins of health and disease (DOHaD). The DOHaD hypothesis suggests that exposure to an adverse environment in fetal life or early childhood leads to permanent changes in organ structure or function, which may have effects on later life health.7,8 Many associations of early life adverse exposures, such as maternal obesity, smoking, air pollution and suboptimal diet, with common diseases throughout the life course have been described.9–12 Long-lasting DNA methylation modifications may be an important mechanism linking early life exposures with outcomes in later life.13 Besides having a potential mechanistic role, DNA methylation may also serve as a biomarker of exposures or outcomes, even without it having a direct causal role in the process.3,14,15 For example, an environmental factor may cause both a change in phenotype and a change in DNA methylation, without a causal relation between the two. Also, a disease could cause a change in DNA methylation, rather than the other way around.15 The ability of methylation signals to serve as strong biomarkers of some exposures, such as maternal smoking in pregnancy, may complicate inference about the role in mediating health outcomes; measurement error correction may help in this regard.16 Various pregnancy, birth and childhood studies have recently initiated research on the role of DNA methylation in the response to environmental exposures and development of health outcomes. Individual studies usually have sample sizes too small to address this issue, but it can be studied in joint efforts of prospective cohort studies starting from early life onwards.1,17 The potential of collaborative efforts between large-scale prospective cohort studies has been demonstrated by the success of recent genome-wide association studies (GWAS) which have shed light on the genetic background of common diseases as well as their risk factors. These GWAS are characterized by state-of-the-art genome-wide agnostic approaches in which millions of genetic variants are related to a particular health outcome, usually in the setting of large consortia combining the results of multiple studies, using meta-analysis. Common genetic variants have been identified that are related to birthweight, childhood obesity, respiratory phenotypes, atopic dermatitis and behavioural outcomes among others.18–25 In line with these approaches, recent developments enable analysis of hundreds of thousands of DNA methylation markers across the genome on a single array.26,27 The high-throughput and cost-effective nature of these arrays has made it possible for studies to measure DNA methylation across the genome (‘epigenome-wide DNA methylation’) in relatively large samples sizes. These data can be used in epigenome-wide association studies (EWAS) to evaluate associations of DNA methylation at specific sites or regions of the genome with determinants and outcomes of health and disease. EWAS in pregnancy, birth or child cohorts specifically enable exploration of associations of early life exposures with DNA methylation levels in children, and of DNA methylation levels with specific growth, development and health outcomes. Recent study-specific EWAS have shown associations of DNA methylation levels in offspring with birthweight, maternal body mass index and maternal smoking.28–31 Large sample sizes are required to achieve optimal power in analyses of so many genomic sites, especially if the prevalence of the exposure or outcome under study is low. Collaboration between studies and combined meta-analysis of the available data are needed to optimize the use of resources and to increase the likelihood of detecting DNA methylation differences underlying the associations of early life exposures and health outcomes. This paper describes the global Pregnancy And Childhood Epigenetics (PACE) Consortium which, to date, brings together 39 studies with over 29 000 samples and DNA methylation data in pregnant women, newborns and/or children. Besides strongly increased power to detect associations, bringing studies together in the PACE Consortium for meta-analysis greatly decreases the risk of false-positive associations. The larger power also enables more detailed studies into potential causal roles of methylation, using a mendelian randomization approach for which large sample sizes are typically needed. In addition, a number of studies have measured DNA methylation at multiple time points from birth through childhood and/or in adolescence, which enables investigation into the persistence of differential DNA methylation signals over time. Also, the availability of information from studies with participants from various backgrounds in terms of ethnicity, location and living environment enables testing of identified associations across different settings and evaluation of heterogeneity of effects across study populations. The primary aim of the PACE Consortium is to identify differences in DNA methylation in relation to a wide range of exposures and outcomes pertinent to health in pregnancy and childhood through joint analysis of DNA methylation data. Secondary aims of the Consortium are to perform further functional annotation-based analyses, to attempt to assess causality of DNA methylation differences for child health phenotypes, to contribute to methodological development and to exchange knowledge and skills. In June 2013, an international group of studies focused on maternal and child health met at the U.S. National Institute of Environmental Health Sciences to organize an EWAS meta-analysis on maternal smoking in pregnancy and DNA methylation in newborns and children.32 This marked the start of the PACE Consortium. The success of this initial effort resulted in the expansion of the Consortium and inclusion of additional research groups, to include additional exposures and outcomes. The PACE Consortium is modelled after successful GWAS consortia, in which many PACE the Early the Early and Consortium and the for and in Currently, the PACE Consortium 39 studies with genome-wide DNA methylation data from pregnancy, or childhood samples and information on at of the exposures or outcomes of of studies in the PACE Consortium with study information is shown in detailed of the cohorts can be in the and available at The PACE Consortium is an dynamic and additional research are to of studies in the PACE Consortium with study information not study refers to the underlying study from which the EWAS of studies in the PACE Consortium with study information not study refers to the underlying study from which the EWAS The Consortium structure is The in the Consortium is strongly can an are by or more from different This and exchange of knowledge and for both and most or the under the of a more from their or The group as the meta-analysis for a specific For a group is and studies can into or of that specific are to a analysis which inclusion and phenotype and usually or cohort its and of the EWAS data. have shown a influence of different between cohorts on the results of EWAS cohort analyses its data to the analysis after which the results are with the meta-analysis exchange is for usually through These results include the and sample for CpG In meta-analysis of results is the approach and data are between the data approaches may be on and which may for but such approaches have not been used so the meta-analysis of the results and with specific meta-analysis such as include of the of and across and of cohort and meta-analysis The process of and meta-analysis is by an from of the other studies as a a as many studies as possible are in the meta-analysis to increase power to DNA methylation of is in further studies that to in the if After the meta-analysis is further is in terms of and of the analyses using available and analyses (Figure such a of the in of different than in the For example, after a analysis in a of the in childhood and samples may be to study persistence of the identified of the in the PACE Consortium are by the are by the National Institute of Environmental Health Sciences in and analyses are in which In addition, analysis may have if needed. The PACE Consortium brings together a large number of of with 1). studies have data and Many of the cohorts have multiple time points from fetal life into and have into or early have information on maternal exposures pregnancy, maternal smoking and body mass number of studies also information on more specific exposures, such as air cohorts have information on child and/or studies have a particular such as and or but most are cohorts a of data on many These include and respiratory as well as childhood of data and sample in studies can be in The PACE Consortium is focused the common methylation to the PACE Consortium on a are not in PACE with their but rather or not It is possible that a particular study is not in a PACE on a specific for to a or are in on that In such studies of the and are not the is sample and data expansion in increased DNA methylation and phenotype be available in the cohorts have of DNA methylation, and on the persistence of DNA methylation signals are of outcomes and enable specific developmental or life course analyses in relation to DNA methylation are in the and studies in the PACE Consortium have common of DNA methylation. the used by the group is the the most used in large-scale human studies a studies using this can be in the Consortium in the The 000 DNA methylation sites, than of sites across the genome. It is at and CpG and sites on of an international group of DNA methylation The PACE Consortium on exposures pregnancy and childhood health outcomes. studies, a number of exposures and outcomes are available and studies usually in multiple The exposures that the PACE Consortium on are the outcomes are childhood health and is in have methodological such as and evaluation of for methylated Many of the studies in the PACE Consortium also have GWAS data and other of and if the for The availability of GWAS data enables analyses of associations of genetic variants with DNA methylation, as well as analyses to assess the potential influence of genetic on methylation the possible causal role of DNA methylation differences using a mendelian randomization and for genetic markers of exposures, outcomes and methodological in the PACE Consortium. number of the cohorts in the PACE Consortium have EWAS on various phenotypes, maternal smoking, maternal body mass maternal and child and PACE on these studies have between a of the PACE In addition, of the PACE Consortium have to methodological developments in the such as evaluation of of study and analysis are or to the The large PACE Consortium meta-analysis on the results of a meta-analysis on maternal smoking in relation to DNA This meta-analysis of EWAS on maternal smoking pregnancy in with a of There methylated CpG sites in relation to maternal smoking pregnancy, after multiple testing correction using a of of which not been identified for their association with either maternal smoking pregnancy or smoking in This analysis the increased power by large of that most of these DNA methylation signals at birth into but are number of the methylated CpG sites in or with roles in diseases with maternal smoking, such as and also in developmental The a meta-analysis of the association of maternal levels pregnancy among newborns from methylation of CpG sites related to with most of these having in The most recent meta-analysis the results of an of the association of air pollution exposure and DNA methylation in It that exposure to pregnancy with differential offspring DNA methylation in as well as in in of these associations also to of from the PACE Consortium can be analyses can DNA methylation sites, in a brings it sample the of and the use of it the potential for analyses of DNA methylation signals at various throughout childhood and this setting it possible to effects between different and a setting of across studies, the of false-positive results from EWAS analyses in pregnancy, birth and child cohort studies an potential to shed light on underlying the associations of fetal and childhood exposures with later life health and and on a potential role of DNA methylation as a biomarker of exposures or outcomes. The data from early life enables to study the role of DNA methylation in life course health the and backgrounds of the PACE and enables of and to methodological and exchange of knowledge and skills. The of many PACE in consortia, with the studies, of at the start of the PACE Consortium. that may have to consortia, such as between studies, and of the of this the Consortium also for and in their on recent in GWAS consortia, that the PACE structure can be a for both and to for for that additional analyses of exposures or outcomes. to many other consortia, the PACE Consortium has or other than the from the National Institute of Environmental Health Sciences for the and the to of epigenome-wide DNA methylation particular methodological the analyses in the PACE Consortium are mainly on DNA from which are in may have its methylation DNA methylation in not represent DNA methylation in other that may be more for phenotypes, for the association of DNA methylation and This of DNA methylation studies in a in the of the cohort studies not be to more specific with the of be with other in the to be to address of PACE cohorts have DNA methylation measured in the of in samples in response to a 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