Early life is an important window of opportunity to improve health across the full lifecycle. An accumulating body of evidence suggests that exposure to adverse stressors during early life leads to developmental adaptations, which subsequently affect disease risk in later life. Also, geographical, socio-economic, and ethnic differences are related to health inequalities from early life onwards. To address these important public health challenges, many European pregnancy and childhood cohorts have been established over the last 30 years. The enormous wealth of data of these cohorts has led to important new biological insights and important impact for health from early life onwards. The impact of these cohorts and their data could be further increased by combining data from different cohorts. Combining data will lead to the possibility of identifying smaller effect estimates, and the opportunity to better identify risk groups and risk factors leading to disease across the lifecycle across countries. Also, it enables research on better causal understanding and modelling of life course health trajectories. The EU Child Cohort Network, established by the Horizon2020-funded LifeCycle Project, brings together nineteen pregnancy and childhood cohorts, together including more than 250,000 children and their parents. A large set of variables has been harmonised and standardized across these cohorts. The harmonized data are kept within each institution and can be accessed by external researchers through a shared federated data analysis platform using the R-based platform DataSHIELD, which takes relevant national and international data regulations into account. The EU Child Cohort Network has an open character. All protocols for data harmonization and setting up the data analysis platform are available online. The EU Child Cohort Network creates great opportunities for researchers to use data from different cohorts, during and beyond the LifeCycle Project duration. It also provides a novel model for collaborative research in large research infrastructures with individual-level data. The LifeCycle Project will translate results from research using the EU Child Cohort Network into recommendations for targeted prevention strategies to improve health trajectories for current and future generations by optimizing their earliest phases of life. ; The LifeCycle project received funding from the European Union's Horizon 2020 research and innovation programme (Grant Agreement No. 733206 LifeCycle). All study specific acknowledgements and funding are presented in the supplementary materials. This manuscript reflects only the author's view and the Commission is not responsible for any use that may be made of the information it contains
AbstractAltered patterns of facial expression recognition (FER) have been linked to internalizing and externalizing problems in school children and adolescents. In a large sample of preschoolers (N = 727), we explored concurrent and prospective associations between internalizing/externalizing problems and FER. Internalizing/externalizing problems were rated by parents at 18 and 36 months using the Child Behavior Checklist. FER was assessed at 36 months using age‐appropriate computer tasks of emotion matching and emotion labeling. Internalizing problems were associated with emotion‐specific differences at both ages: at 18 months they predicted more accurate labeling of sadness; at 36 months they were associated with less accurate labeling of happiness and anger. Externalizing problems at both ages were associated with general FER deficits, particularly for matching emotions. Findings suggest that in preschoolers, internalizing problems contribute to emotion‐specific differences in FER, while externalizing problems are associated with more general FER deficits. Knowledge of the specific FER patterns associated with internalizing/externalizing problems can be proven useful in the refinement of emotion‐centered preventive interventions.
Background: Gestational diabetes and gestational hypertensive disorders are associated with offspring obesity, but the role of maternal adiposity in these associations remains unclear. We aimed to investigate whether these pregnancy complications affect the odds of offspring obesity independently of maternal obesity. Methods: We did an individual participant data (IPD) meta-analysis of mother–offspring pairs from prospective birth cohort studies that had IPD on mothers with singleton liveborn children born from 1989 onwards and had information available about maternal gestational diabetes, gestational hypertension or pre-eclampsia, and childhood body-mass index (BMI). We applied multilevel mixed-effects models to assess associations of gestational diabetes, gestational hypertension, and pre-eclampsia with BMI SD scores and the odds of overweight and obesity throughout childhood, adjusting for lifestyle characteristics (offspring's sex, maternal age, educational level, ethnicity, parity, and smoking during pregnancy). We then explored the extent to which any association was explained by maternal pre-pregnancy or early-pregnancy BMI. Findings: 160 757 mother–offspring pairs from 34 European or North American cohorts were analysed. Compared with uncomplicated pregnancies, gestational diabetes was associated with increased odds of overweight or obesity throughout childhood (odds ratio [OR] 1·59 [95% CI 1·36 to 1·86] for early childhood [age 2·0–4·9 years], 1·41 [1·26 to 1·57] for mid childhood [5·0–9·9 years], and 1·32 [0·97 to 1·78] for late childhood [10·0–17·9 years]); however, these associations attenuated towards the null following adjustment for maternal BMI (OR 1·35 [95% CI 1·15 to 1·58] for early childhood, 1·12 [1·00 to 1·25] for mid childhood, and 0·96 [0·71 to 1·31] for late childhood). Likewise, gestational hypertension was associated with increased odds of overweight throughout childhood (OR 1·19 [95% CI 1·01 to 1·39] for early childhood, 1·23 [1·15 to 1·32] for mid childhood, and 1·49 [1·30 to 1·70] for late childhood), but additional adjustment for maternal BMI largely explained these associations (1·01 [95% CI 0·86 to 1·19] for early childhood, 1·02 [0·95 to 1·10] for mid childhood, and 1·18 [1·03 to 1·36] for late childhood). Pre-eclampsia was associated with decreased BMI in early childhood only (difference in BMI SD score −0·05 SD score [95% CI −0·09 to −0·01]), and this association strengthened following additional adjustment for maternal BMI. Interpretation: Although lowering maternal risk of gestational diabetes, gestational hypertension, and pre-eclampsia is important in relation to maternal and fetal pregnancy outcomes, such interventions are unlikely to have a direct impact on childhood obesity. Preventive strategies for reducing childhood obesity should focus on maternal BMI rather than on pregnancy complications. Funding: EU's Horizon 2020 research and innovation programme (LifeCycle Project). ; This study has received support from the US National Institute of Health (R01 DK10324) and European Research Council under the European Union's Seventh 22 Framework Programme (FP7/2007-2013) / ERC grant agreement no 669545. The Swedish Research Council, The Swedish Heart and Lung Foundation, The Swedish Research Council for Working Life and Social Welfare, the Swedish Asthma and Allergy Association Research Foundation, The Swedish Research Council Formas, Stockholm County Council, and the European Commission's Seventh Framework 29 Program MeDALL under grant agreement No. 261357. This study has received support from the British Heart Foundation (CS/16/4/32482), US National Institute of Health (R01 DK10324) and European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement no 669545. The general design of the Generation R Study is made possible by financial support from the Erasmus MC, University Medical Center, Rotterdam, Erasmus University Rotterdam, Netherlands Organization for Health Research and Development (ZonMw), Netherlands Organisation for Scientific Research (NWO), Ministry of Health, Welfare and Sport and Ministry of Youth and Families. Research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007- 2013), project EarlyNutrition under grant agreement n°289346, the European Union's Horizon 2020 research and innovation programme under grant agreement No 633595 (DynaHEALTH) and the European Union's Horizon 2020 research and innovation programme under grant agreement 733206 (LifeCycle Project). European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreements Early Nutrition n° 289346 and by funds from the Norwegian Research Council's MILPAAHEL programme, project No.213148. This study was funded by Grants from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), Spain: ISCIII (G03/176; FIS-FEDER: PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, and PI16/1288; Miguel Servet-FEDER CP11/00178, CP15/00025, and CPII16/00051), and Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249). The "Rhea" project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-28.1.2.1.4 envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX) and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011-2014; "Rhea Plus": Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-15). ROLO is supported by the Health Research Board Ireland, the Health Research Centre for Health and Diet Research, and the European Union's Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition under grant agreement no. 289346. The SWS is supported by grants from the Medical Research Council, National Institute for Health Research Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton National Health Service Foundation Trust, and the European Union's Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition (grant 289346). Study participants were drawn from a cohort study funded by the Medical Research Council and the Dunhill Medical Trust.
Background: Infant weight gain is associated with lower lung function and a higher risk of childhood asthma. Detailed individual childhood growth patterns might be better predictors of childhood respiratory morbidity than the difference between two weight and height measurements. We assessed the associations of early childhood growth patterns with lung function and asthma at the age of 10 years and whether the child's current body mass index (BMI) influenced any association. Methods: We derived peak height and weight growth velocity, BMI at adiposity peak, and age at adiposity peak from longitudinally measured weight and height data in the first 3 years of life of 4435 children enrolled in a population-based prospective cohort study. At 10 years of age, spirometry was performed and current asthma was assessed by questionnaire. Spirometry outcomes included forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio, and forced expiratory flow after exhaling 75% of vital capacity (FEF75). Results: Greater peak weight velocity was associated with higher FVC but lower FEV1/FVC and FEF75. Greater BMI at adiposity peak was associated with higher FVC and FEV1 but lower FEV1/FVC and FEF75. Greater age at adiposity peak was associated with higher FVC, FEV1, FEV1/FVC and FEF75, particularly in children with a small size at birth, and lower odds of current asthma in boys. The child's current BMI only explained the associations of peak weight velocity and BMI at adiposity peak with FVC and FEV1. Peak height velocity was not consistently associated with impaired lung function or asthma. Conclusion: Peak weight velocity and BMI at adiposity peak were associated with reduced airway patency in relation to lung volume, whereas age at adiposity peak was associated with higher lung function parameters and lower risk of asthma at 10 years, particularly in boys. ; The Generation R Study is made possible by financial support from the Erasmus Medical Centre, Rotterdam, Erasmus University Rotterdam and the Netherlands Organization for Health Research and Development. Dr Liesbeth Duijts received additional funding from the European Union's Horizon 2020 co-funded programme ERA-Net on Biomarkers for Nutrition and Health (ERA HDHL) (ALPHABET project (no. 696295; 2017), ZonMW The Netherlands (no. 529051014; 2017)). The study was supported by the Netherlands Organization for Health Research and Development (VIDI 016.136.361), a European Research Council Consolidator Grant (ERC-2014-CoG-648916), funding from the European Union's Seventh Framework Programme under grant agreement no. 289346 (EarlyNutrition), and funding from the European Union's Horizon 2020 research and innovation programme under grant agreements no. 733206 (LifeCycle) and no. 633595 (DynaHEALTH). Dr Maribel Casas received funding from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness) (CD12/00563 and MS16/00128). The researchers are independent from the funders.
AbstractThis exploratory study aimed to examine which components of early childhood conscience predicted bullying involvement around school entry. In the population‐based Generation R Study, teacher reports of bullying involvement and parent reports of conscience were available for 3,244 children (M age = 6.7 years). Higher levels of overall conscience predicted lower bullying perpetration scores, independently of intelligence quotient, temperamental traits and sociodemographic characteristics. Particularly, the subscales guilt, confession, and internalized conduct, and to a lesser extent empathy, predicted bullying perpetration. Conscience was not related to victimization. Similar results were found using observations during so‐called 'cheating games' (subsample N = 450 children). Findings suggest that improving children's understanding of moral standards and norms may be a potential target for bullying intervention programs in early primary school.
Research described risk factors for maternal use of harsh discipline, but knowledge about determinants of paternal harsh discipline is lacking. This study aimed to identify determinants of harsh discipline and whether this differed between mothers and fathers. Harsh disciplining practices were self‐reported by Dutch parents of 3‐year‐old children. Data were available for 3,756 children and both parents. Younger parental age, non‐Western national origin, family dysfunction, psychopathology, and delinquency history were independently associated with an increased risk of maternal and paternal harsh discipline. Indicators of socioeconomic status (e.g., financial difficulties and educational level) were also associated with harsh discipline, but in mothers only. Our results suggest that preventive interventions should ideally be applied early in children's lives or even before birth, given the prevalence of parental harsh discipline in young children. These interventions should have a special focus on socially disadvantaged families and on parents with psychopathology and family stress.
This study examined hostility and harsh discipline of both mothers and fathers as potential mechanisms explaining the association between a maternal maltreatment history and her offspring's internalizing and externalizing problems. Prospective data from fetal life to age 6 were collected from a total of 4,438 families participating in the Generation R Study. Maternal maltreatment was assessed during pregnancy using a self-administered questionnaire. Mothers and fathers each reported on their psychological distress and harsh discipline when the child was 3 years. Children's internalizing and externalizing problems were assessed by parental reports and child interview at age 6. Findings from structural equation modeling showed that the association between a maternal maltreatment history and her offspring's externalizing problems was explained by maternal hostility and harsh discipline and, at least partially, also by paternal hostility and harsh discipline. Child interview data provided support for both these indirect paths, with associations largely similar to those observed for parent reports.
Background: Air pollution exposure during fetal life has been related to impaired child neurodevelopment, but it is unclear if brain structural alterations underlie this association. The authors assessed whether air pollution exposure during fetal life alters brain morphology and whether these alterations mediate the association between air pollution exposure during fetal life and cognitive function in school-age children. Methods: We used data from a population-based birth cohort set up in Rotterdam, The Netherlands (2002–2006). Residential levels of air pollution during the entire fetal period were calculated using land-use regression models. Structural neuroimaging and cognitive function were performed at 6 to 10 years of age (n = 783). Models were adjusted for several socioeconomic and lifestyle characteristics. Results: Mean fine particle levels were 20.2 μg/m3 (range, 16.8–28.1 μg/m3). Children exposed to higher particulate matter levels during fetal life had thinner cortex in several brain regions of both hemispheres (e.g., cerebral cortex of the precuneus region in the right hemisphere was 0.045 mm thinner (95% confidence interval, 0.028–0.062) for each 5-μg/m3 increase in fine particles). The reduced cerebral cortex in precuneus and rostral middle frontal regions partially mediated the association between exposure to fine particles and impaired inhibitory control. Air pollution exposure was not associated with global brain volumes. Conclusions: Exposure to fine particles during fetal life was related to child brain structural alterations of the cerebral cortex, and these alterations partially mediated the association between exposure to fine particles during fetal life and impaired child inhibitory control. Such cognitive impairment at early ages could have significant long-term consequences. ; This work was supported by European Community Seventh Framework Program Grant Nos. GA#211250 (to BB) and GA#243406 (BB; principal investigator, Ranjeet S. Sokhi) for air pollution exposure assessment; The Netherlands Organization for Health Research and Development (Geestkracht Program Grant No. 10.000.1003 (to HT) and Grant No. TOP 40-00812-98-11021 [to TW]); the Health Effects Institute, an organization jointly funded by the U.S. Environmental Protection Agency (Assistance Award Grant No. R-82811201), and certain motor vehicle and engine manufacturers (to MG); The Netherlands Organization for Health Research and Development Grant Nos. VIDI 016.136.361 (to VWVJ) and The Netherlands Organization for Scientific Research Grant No. 016.VICI.170.200 (to HT); European Research Council Grant No. ERC-2014-CoG-64916 (to VWVJ); European Union Horizon 2020 research and innovation program Grant Nos. 633595 (DynaHEALTH) (to HT) and 733206 (LifeCycle) (to VWVJ); a personal fellowship (EUR Fellow 2014) from the Erasmus University Rotterdam (to HEM); and Miguel Servet fellowship Grant Nos. MS13/00054 and CP13/00054 (to MG) awarded by the Spanish Institute of Health Carlos III (Ministry of Economy and Competitiveness).
Background: Air pollution has been related to brain structural alterations, but a relationship with white matter microstructure is unclear. Objectives: We assessed whether pregnancy and childhood exposures to air pollution are related to white matter microstructure in preadolescents. Methods: We used data of 2,954 children from the Generation R Study, a population-based birth cohort from Rotterdam, Netherlands (2002-2006). Concentrations of 17 air pollutants including nitrogen oxides (NOX), particulate matter (PM), and components of PM were estimated at participants' homes during pregnancy and childhood using land-use regression models. Diffusion tensor images were obtained at child's 9-12 years of age, and fractional anisotropy (FA) and mean diffusivity (MD) were computed. We performed linear regressions adjusting for socioeconomic and lifestyle characteristics. Single-pollutant analyses were followed by multipollutant analyses using the Deletion/Substitution/Addition (DSA) algorithm. Results: In the single-pollutant analyses, higher concentrations of several air pollutants during pregnancy or childhood were associated with significantly lower FA or higher MD (p<0.05). In multipollutant models of pregnancy exposures selected by DSA, higher concentration of fine particles was associated with significantly lower FA [−0.71 (95% CI: −1.26, −0.16) per 5μg/m3 fine particles] and higher concentration of elemental silicon with significantly higher MD [0.06 (95% CI: 0.01, 0.11) per 100ng/m3 silicon]. Multipollutant models of childhood exposures selected by DSA indicated significant associations of NOX with FA [−0.14 (95% CI: −0.23, −0.04) per 20-μg/m3 NOX increase], and of elemental zinc and the oxidative potential of PM with MD [0.03 (95% CI: 0.01, 0.04) per 10-ng/m3 zinc increase and 0.07 (95% CI: 0.00, 0.44) per 1-nmolDTT/min/m3 oxidative potential increase]. Mutually adjusted models of significant exposures during pregnancy and childhood indicated significant associations of silicon during pregnancy, and zinc during childhood, with MD. Discussion: Exposure in pregnancy and childhood to air pollutants from tailpipe and non-tailpipe emissions were associated with lower FA and higher MD in white matter of preadolescents. https://doi.org/10.1289/EHP4709. ; The general design of the Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam; the Erasmus University Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); the Netherlands Organization for Scientific Research (NWO); and the Ministry of Health, Welfare and Sport. Air pollution exposure assessment was made possible by funding from the European Community's Seventh Framework Program (Grant Agreement no. 211250, Grant Agreement no. 243406). In addition, the study was made possible by financial support from the ZonMw (Geestkracht Program 10.000.1003 and TOP 40-00812-98-11021). Neuroimaging was supported by the ZonMw TOP project no. 91211021 to T.W., Sophia Foundation Project S18-20 to R.L.M., and super computing computations for imaging processing were supported by the NWO Physical Sciences Division (Exacte Wetenschappen) and SURFsara (Cartesius compute cluster, https://www.surf.nl). Research described in this article was also conducted under contract to the HEI, an organization jointly funded by the U.S. EPA (Assistance Award No. R-82811201) and certain motor vehicle and engine manufacturers. The contents of this article do not necessarily reflect the views of HEI, or its sponsors, nor do they necessarily reflect the views and policies of the U.S. EPA or motor vehicle and engine manufacturers. V.W.V.J. and H.T. received funding from the ZonMw (VIDI 016.136.361 and NWO-grant 016.VICI.170.200, respectively), the European Research Council (ERC-2014-CoG-64916), and the European Union's Horizon 2020 research and innovation program under grant agreement no. 633595 (DynaHEALTH) and no. 733206 (LifeCycle). H.E.M. was supported by Stichting Volksbond Rotterdam and the Dutch Brain Foundation (De Hersenstichting, project number GH2016.2.01), and by the 2019 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. M.G. is funded by a Miguel Servet fellowship (MS13/00054, CP13/00054, CI18/00018) awarded by the Spanish Institute of Health Carlos III. W.D. is funded in part by the Research Council of Norway (RCN) (grant 249779) and through the RCN Centers of Excellence funding scheme (grant 262700).
BACKGROUND: Little is known about developmental neurotoxicity of particulate matter composition. We aimed to investigate associations between exposure to elemental composition of outdoor PM2.5 at birth and cognitive and psychomotor functions in childhood. METHODS: We analyzed data from 4 European population-based birth cohorts in the Netherlands, Germany, Italy and Spain, with recruitment in 2000-2006. Elemental composition of PM2.5 measurements were performed in each region in 2008-2011 and land use regression models were used to predict concentrations at participants' residential addresses at birth. We selected 8 elements (copper, iron, potassium, nickel, sulfur, silicon, vanadium and zinc) and used principal component analysis to combine elements from the same sources. Cognitive (general, verbal, and non-verbal) and psychomotor (fine and gross) functions were assessed between 1 and 9years of age. Adjusted cohort-specific effect estimates were combined using random-effects meta-analysis. RESULTS: 7246 children were included in this analysis. Single element analysis resulted in negative association between estimated airborne iron and fine motor function (-1.25 points [95% CI -2.45 to -0.06] per 100ng/m3 increase of iron). Association between the motorized traffic component, derived from principal component analysis, and fine motor function was not significant (-0.29 points [95% CI -0.64 to 0.06] per unit increase). None of the elements were associated with gross motor function or cognitive function, although the latter estimates were predominantly negative. CONCLUSION: Our results suggest that iron, a highly prevalent element in motorized traffic pollution, may be a neurotoxic compound. This raises concern given the ubiquity of motorized traffic air pollution. ; This work was supported by the European Community's Seventh Framework Program (FP7/ 2007–2011), grant agreements 211250 and 243406. The European Union's Horizon 2020 Research and Innovation Program (no.: 633595, DynaHealth) and also received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement no. 733206 (LifeCycle). Also by the EU Commission (261357).
Background: studies examining associations of early-life cat and dog ownership with childhood asthma have reported inconsistent results. Several factors could explain these inconsistencies, including type of pet, timing, and degree of exposure. Objective: our aim was to study associations of early-life cat and dog ownership with asthma in school-aged children, including the role of type (cat vs dog), timing (never, prenatal, or early childhood), and degree of ownership (number of pets owned), and the role of allergic sensitization. Methods: we used harmonized data from 77,434 mother-child dyads from 9 birth cohorts in the European Union Child Cohort Network when the child was 5 to 11 years old. Associations were examined through the DataSHIELD platform by using adjusted logistic regression models, which were fitted separately for each cohort and combined by using random effects meta-analysis. Results: the prevalence of early-life cat and dog ownership ranged from 12% to 45% and 7% to 47%, respectively, and the prevalence of asthma ranged from 2% to 20%. There was no overall association between either cat or dog ownership and asthma (odds ratio [OR] = 0.97 [95% CI = 0.87-1.09] and 0.92 [95% CI = 0.85-1.01], respectively). Timing and degree of ownership did not strongly influence associations. Cat and dog ownership were also not associated with cat- and dog-specific allergic sensitization (OR = 0.92 [95% CI = 0.75-1.13] and 0.93 [95% CI = 0.57-1.54], respectively). However, cat- and dog-specific allergic sensitization was strongly associated with school-age asthma (OR = 6.69 [95% CI = 4.91-9.10] and 5.98 [95% CI = 3.14-11.36], respectively). There was also some indication of an interaction between ownership and sensitization, suggesting that ownership may exacerbate the risks associated with pet-specific sensitization but offer some protection against asthma in the absence of sensitization. Conclusion: our findings do not support early-life cat and dog ownership in themselves increasing the risk of school-age ...
Background: Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes. Objectives: We aimed to investigate associations between prenatal exposure to particulate matter (PM) with diameter <10 (PM10) or <2.5 mu m (PM2.5) and DNA methylation in newborns and children. Methods: We meta-analyzed associations between exposure to PM10 (n=1,949) and PM2.5 (n=1,551) at maternal home addresses during pregnancy and newborn DNA methylation assessed by Illumina Infinium HumanMethylation450K BeadChip in nine European and American studies, with replication in 688 independent newborns and look-up analyses in 2,118 older children. We used two approaches, one focusing on single cytosine-phosphate-guanine (CpG) sites and another on differentially methylated regions (DMRs). We also related PM exposures to blood mRNA expression. Results: Six CpGs were significantly associated [false discovery rate (FDR) <0.05] with prenatal PM10 and 14 with PM2.5 exposure. Two of the PM10-related CpGs mapped to FAM13A (cg00905156) and NOTCH4 (cg06849931) previously associated with lung function and asthma. Although these associations did not replicate in the smaller newborn sample, both CpGs were significant (p<0.05) in 7- to 9-y-olds. For cg06849931, however, the direction of the association was inconsistent. Concurrent PM10 exposure was associated with a significantly higher NOTCH4 expression at age 16 y. We also identified several DMRs associated with either prenatal PM10 and or PM2.5 exposure, of which two PM10-related DMRs, including H19 and MARCH11, replicated in newborns. Conclusions: Several differentially methylated CpGs and DMRs associated with prenatal PM exposure were identified in newborns, with annotation to genes previously implicated in lung-related outcomes. ; ALSPAC: The UK Medical Research Council and the Wellcome Trust (Grant ref. 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and P.Y. will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristoLac.uk/alspac/external/documents/grant-acknowledgements.pdf). This research was specifically funded by a joint grant from the UK Economic & Social and Biotechnology & Biological Sciences Research Councils (Grant ref. ES/N000498/1). ALSPAC was funded by the BBSRC (BBI025751/1 and BB/I025263/1). Air pollution exposure assessment was funded by Public Health England as part of the MRC-PHE Centre for Environment and Health, funded also by the UK Medical Research Council (Grant ref. MR/L01341X/1). This paper does not necessarily reflect the views of Public Health England or the Department of Health. BAMSE was supported by The Swedish Research Council, The Swedish Heart-Lung Foundation, Freemason Child House Foundation in Stockholm, MeDALL (Mechanisms of the Development of ALLergy) a collaborative project conducted within the European Union (grant agreement No. 261357), Centre for Allergy Research, Stockholm County Council (ALE), Swedish Foundation for Strategic Research (SSF) (RBc08-0027), the Strategic Research Programme (SFO) in Epidemiology at Karolinska Institutet, The Swedish Research Council Foams, and the Swedish Environment Protection Agency. E.M. is supported by a grant from the European Research Council under the European Union (EU) Horizon 2020 (H2020) research and innovation programme (grant agreement number 757919, TRIBAL). O.G. is supported by Forte (Swedish Research Council for Health, Working Life and Welfare) and The Swedish Society for Medical Research. CHS: This work was supported by NIEHS grants K01ES017801, R01ES022216, and P30ES007048. EARLI: This work was supported by NIH grants R01ES016443, R01ES023780, and R01ES017646 as well as by Autism Speaks (AS 5938). ENVIRONAGE: The ENVIRONAGE birth cohort is funded by the European Research Counsil (ERC-2012-StG.310898) and by funds of the Flemisch Scientific Research Council (FWO, N1516112/G.0.873.11N.10). The methylation assays were funded by the European Community's Seventh Framework Programme FP7/2007-2013 project EXPOsOMICS (grant no. 308610). Z.H. is supported by the Exposomics EC FP7 grant (Grant agreement no. 308610). ZH and A.G. and the Epigenetics Group at IARC are supported by grants from the Institut National du Cancer (INCa, Plan Cancer-EVA-Inserm, France) and Association pour la Recherche sur le Cancer (ARC, France). Generation R Study: The general design of the Generation R Study is made possible by financial support from the Erasmus Medical Center (MC), Rotterdam, the Erasmus University Rotterdam, Netherlands Organization for Health Research and Development and the Ministry of Health, Welfare and Sport. The EWAS data was funded by a grant to VWJ from Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA; project no. 050-060-810), by funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC. V.W.J. also received a grant from Netherlands Organization for Health Research and Development (VIDI 016.136.361) and a Consolidator Grant from the European Research Council (ERC-2014-CoG-648916). J.F.F. has received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement no. 633595 (DynaHEALTH). This project received funding from the European Union's Horizon 2020 Research and Innovation Programme (733206, LIFECYCLE). HELIX: The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333 - the HELIX project. R.G. received the grant of the Lithuanian Agency for Science Innovation and Technology (No. 45 31V-66). The Norwegian Mother and Child Cohort Study (MoBa) is supported by the Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no. N01-ES-75558), NIH/NINDS (grant no. 1 UO1 NS 047537-01 and grant no. 2 UO1 NS 047537-06A1). INMA: This study was funded by grants from Institut() de Salud Carlos III (Red INMA G03/176), Generalitat de Catalunya-CIRIT 1999SGR 00241, and EU Commission (261357; 211250; 268479). Piccolipiu: The study was approved and initially funded by the Italian National Centre for Disease Prevention and Control (CCM grant 2010) and by the Italian Ministry of Health (art 12 and 12bis Dl.gs.vo 502/92). The methylation assays were funded by the European Community's Seventh Framework Programme FP7/2007-2013 project EXPOsOMICS (grant no. 308610). Z.H. is supported by the Exposomics EC FP7 grant (Grant agreement no: 308610). Z.H. and A.G. and the Epigenetics Group at IARC are supported by grants from the Institut National du Cancer (INCa, Plan Cancer-EVA-INSERM, France) and Association pour la Recherche sur le Cancer (ARC, France). Rhea: The methylation assays were funded by the European Community's Seventh Framework Programme FP7/2007-2013 project EXPOsOMICS (grant no. 308610). Z.H. is supported by the Exposomics EC FP7 grant (grant agreement no. 308610). ZH and A.G. and the Epigenetics Group at IARC are supported by grants from the Institut National du Cancer (INCa, Plan Cancer-EVA INSERM, France) and Association pour la Recherche sur le Cancer (ARC, France). PRISM: R.J.W. received funding for the PRISM cohort under HL095606 and R01 HL1143396. A.C.J. is supported by R00 ES023450. Project Viva: This Project Viva study was supported by grants from the NIH (NIH R01 HL 111108, R01 NR013945, R01 HD 034568, K24 HD069408, K23 ES022242, P01ES009825, R01AI102960, P30 ES000002) and the U.S. Environmental Protection Agency (EPA) (R832416, RD834798). This publication's contents are solely the responsibility of the grantee and do not necessarily represent the official views of the U.S. Government, the U.S. Department of Health and Human Services or the NIH, or the EPA. Further, the EPA does not endorse the purchase of any commercial products or services mentioned in the publication. MeDALL: The methylation study of MeDALL cohorts was funded by MEDALL, a collaborative project supported by the European Union under the Health Cooperation Work Programme of the 7th Framework Programme (grant agreement no. 261357). The Biobank-Based Integrative Omics Studies (BIOS) Consortium is funded by BBMRI-NL, a research 'infrastructure financed by the Dutch government (NWO 184.021.007). BAMSE: We would like to thank all the families for their participation in the BAMSE study. In addition, we would like to thank E. Haliner, S. Nilsson, and A. Lauber at the BAMSE secretary for invaluable support, as well as Mutation Analysis Facility (MAF) at Karolinska Institutet for genome-wide methylation analysis, and I. Delin for excellent technical assistance. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project b201.4110.
