Epigenome-wide association of father's smoking with offspring DNA methylation: a hypothesis-generating study

Epidemiological studies suggest that father’s smoking might influence their future children’s health, but few studies have addressed whether paternal line effects might be related to altered DNA methylation patterns in the offspring. To investigate a potential association between fathers’ smoking exposures and offspring DNA methylation using epigenome-wide association studies. We used data from 195 males and females (11–54 years) participating in two population-based cohorts. DNA methylation was quantified in whole blood using Illumina Infinium MethylationEPIC Beadchip. Comb-p was used to analyse differentially methylated regions (DMRs). Robust multivariate linear models, adjusted for personal/maternal smoking and cell-type proportion, were used to analyse offspring differentially associated probes (DMPs) related to paternal smoking. In sensitivity analyses, we adjusted for socio-economic position and clustering by family. Adjustment for inflation was based on estimation of the empirical null distribution in BACON. Enrichment and pathway analyses were performed on genes annotated to cytosine-phosphate-guanine (CpG) sites using the gometh function in missMethyl. We identified six significant DMRs (Sidak-corrected P values: 0.0006–0.0173), associated with paternal smoking, annotated to genes involved in innate and adaptive immunity, fatty acid synthesis, development and function of neuronal systems and cellular processes. DMP analysis identified 33 CpGs [false discovery rate (FDR)  < 0.05]. Following adjustment for genomic control (λ = 1.462), no DMPs remained epigenome-wide significant (FDR < 0.05). This hypothesis-generating study found that fathers’ smoking was associated with differential methylation in their adolescent and adult offspring. Future studies are needed to explore the intriguing hypothesis that fathers’ exposures might persistently modify their future offspring’s epigenome.publishedVersio

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders

Diagnosis and management of Silver–Russell syndrome: first international consensus statement

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver–Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood

A Pregnancy and Childhood Epigenetics Consortium (PACE) meta-analysis highlights potential relationships between birth order and neonatal blood DNA methylation

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: Blood samples and raw genetic data of neonatal subjects from each cohort are governed by their respective institutions and/or government agencies, and mostly could not be shared publicly without specific approvals. For example, for data from first author cohort, California Childhood Leukemia Study (CCLS), we respectfully are unable to share raw, individual genetic data freely with other investigators. Should we be contacted by other investigators who would like to use the data; we will direct them to the California Department of Public Health Institutional Review Board to establish their own approved protocol to utilize the data, which can then be shared peer-to-peer.Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P < 0.05) and 1107 regions. Forty CpGs were located within known quantitative trait loci for gene expression traits in blood, and trait enrichment analysis suggested a strong association with immune-related, transcriptional control, and blood pressure regulation phenotypes. Decreasing fertility rates worldwide with the concomitant increased proportion of first-born children highlights a potential reflection of birth order-related epigenomic states on changing disease incidence trends.National Institute of Environmental Health SciencesNational Cancer InstituteUS Environmental Protection Agenc

Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

Background Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 x 10(- 7), of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects

Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude

This is the final version. Available from BMC via the DOI in this record. Individual cohort-level data can be obtained from the respective cohort (see Additional file 1: Table S1 and Additional file 2 for cohort details).BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N). CONCLUSIONS: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.Wellcome TrustBiotechnology and Biological Sciences Research Council (BBSRC)Biotechnology and Biological Sciences Research Council (BBSRC)European Union’s Horizon 2020Economic and Social Research Council (ESRC)Medical Research Council (MRC)Medical Research Council (MRC)European UnionSwedish foundation for strategic research (SSF)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)Environmental Protection Agency (EPA)National Cancer Institute Cancer CenterNational Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)Environmental Protection Agency (EPA)Environmental Protection Agency (EPA)European UnionEuropean UnionEuropean UnionEuropean UnionEuropean Union’s Horizon 2020European Research Council (ERC)German Ministry of Education and ResearchNational Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)Autism SpeaksNational Institutes of Health (NIH)National Institutes of Health (NIH)European UnionEuropean UnionEuropean UnionEuropean UnionEuropean UnionEuropean UnionEuropean UnionEuropean UnionEuropean UnionEuropean Research Council (ERC)Flemisch Scientific Research CouncilFlemisch Scientific Research CouncilFlemisch Scientific Research CouncilEuropean UnionFonds de recherche du Québec - Santé (FRQS)Canadian Institute of Health Research (CIHR)Canadian Institute of Health Research (CIHR)Netherlands Organisation for Scientific Research (NWO)National Institute of Child and Human DevelopmentEuropean Union’s Horizon 2020European Union’s Horizon 2020European Union’s Horizon 2020ZonMwZonMwMedical Research Council Integrative Epidemiology Unit (University of Bristol)Netherlands Heart FoundationNetherlands Heart FoundationNetherlands Organisation for Scientific Research (NWO)European UnionNational Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)Spanish Ministry of ScienceNational Institute for Health and Care Research (NIHR)Wellcome TrustNorwegian Ministry of Health and the Ministry of Education and ResearchNorwegian Ministry of Health and the Ministry of Education and ResearchNorwegian Ministry of Health and the Ministry of Education and ResearchLithuanian Agency for Science Innovation and TechnologySpanish Ministry of HealthSpanish Ministry of HealthSpanish Ministry of HealthSpanish Ministry of HealthSpanish Ministry of HealthInstituto de Salud Carlos IIIInstituto de Salud Carlos IIIEuropean Research Council (ERC)CDMRP/Department of DefenseNIGMSNational Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Asthma Campaign, UKNational Institutes of Health (NIH)Medical Research Council (MRC)National Institutes of Health (NIH)Norwegian Research CouncilNational Institute of Environmental Health SciencesResearch Council of NorwayNational Institute of Environmental Health SciencesNational Institute of Environmental Health SciencesNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institute of Environmental Health SciencesNational Institute of Environmental Health SciencesSwedish Research CouncilSwedish Initiative for research on Microdata in the Social And Medical Sciences (SIMSAM)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)National Institutes of Health (NIH)Medical Research Council Integrative Epidemiology Unit (University of Bristol)Medical Research Council Integrative Epidemiology Unit (University of Bristol)Medical Research Council Integrative Epidemiology Unit (University of Bristol)Swedish Heart-Lung FoundationUniversity of MunichFoundation for Medical Research (FRM)National Agency for ResearchNational Institute for Research in Public HealthFrench Ministry of HealthFrench Ministry of ResearchInserm Bone and Joint Diseases National Research (PRO-A) and Human Nutrition National Research ProgramsParis–Sud UniversityNestléFrench National Institute for Population Health SurveillanceFrench National Institute for Health EducationFrench Agency for Environmental Health SafetyMutuelle Générale de l’Education NationaleFrench National Agency for Food SecurityFrench-speaking association for the study of diabetes and metabolismItalian National Centre for Disease Prevention and ControlItalian Ministry of HealthGreek Ministry of HealthFlemish Government (Department of Economy, Science and Innovations, Agency for Care and Health and Department of Environment)The Research Foundation-FlandersFlemish Institute for Technological ResearchDiabète QuébecErasmus University RotterdamNetherlands Organization for Health Research and Development and the Ministry of Health, Welfare and SportErasmus MCDanish National Research FoundationDanish Regional CommitteesNovo Nordisk FoundationLundbeck FoundationHelmholtz Center for Environmental ResearchGerman Cancer Research CentreAcademy of FinlandEraNetEVOUniversity of Helsinki Research FundsSigne and Ane Gyllenberg foundationEmil Aaltonen FoundationFinnish Medical FoundationJane and Aatos Erkko FoundationJuho Vainio foundationYrjö Jahnsson foundationJalmari and Rauha Ahokas foundationPaivikki and Sakari Sohlberg FoundationSigrid Juselius FoundationSir Jules Thorn Charitable TrustSwedish Asthma and Allergy Association's Research FoundationStiftelsen Frimurare Barnhuset Stockhol

Association of adult lung function with accelerated biological aging

Lung function, strongly associated with morbidity and mortality, decreases with age. This study examines whether poor adult lung function is associated with age accelerations (AAs). DNA methylation (DNAm) based AAs, lifespan predictors (GrimAge and plasminogen activator inhibitor 1-PAI1) and their related age-adjusted measures were estimated from peripheral blood at two time points (8-to-11 years apart) in adults from two cohorts: SAPALDIA (n=987) and ECRHS (n=509). Within each cohort and stratified by gender (except for estimators from GrimAge and PAI1), AAs were used as predictors in multivariate linear regression with cross-sectional lung function parameters, and in covariate-adjusted mixed linear regression with longitudinal change in lung function and meta-analysed. AAs were found cross-sectionally associated with lower mean FEV1 (Forced Expiratory Volume in one second) (AA-residuals:P-value=4x10-4; Intrinsic Epigenetic AA:P-value=2x10-4) in females at the follow-up time point only, and the same trend was observed for FVC (Forced Vital Capacity). Both lifespan and plasma level predictors were observed strongly associated with lung function decline and the decline was stronger in the follow-up time points (strongest association between FEV1 and DNAmAge GrimAge:P-value=1.25x10-17). This study suggests that DNAm based lifespan and plasma level predictors can be utilised as important factors to assess lung health in adults

Epigenome-wide association of father's smoking with offspring DNA methylation: a hypothesis-generating study

Epidemiological studies suggest that father’s smoking might influence their future children’s health, but few studies have addressed whether paternal line effects might be related to altered DNA methylation patterns in the offspring. To investigate a potential association between fathers’ smoking exposures and offspring DNA methylation using epigenome-wide association studies. We used data from 195 males and females (11–54 years) participating in two population-based cohorts. DNA methylation was quantified in whole blood using Illumina Infinium MethylationEPIC Beadchip. Comb-p was used to analyse differentially methylated regions (DMRs). Robust multivariate linear models, adjusted for personal/maternal smoking and cell-type proportion, were used to analyse offspring differentially associated probes (DMPs) related to paternal smoking. In sensitivity analyses, we adjusted for socio-economic position and clustering by family. Adjustment for inflation was based on estimation of the empirical null distribution in BACON. Enrichment and pathway analyses were performed on genes annotated to cytosine-phosphate-guanine (CpG) sites using the gometh function in missMethyl. We identified six significant DMRs (Sidak-corrected P values: 0.0006–0.0173), associated with paternal smoking, annotated to genes involved in innate and adaptive immunity, fatty acid synthesis, development and function of neuronal systems and cellular processes. DMP analysis identified 33 CpGs [false discovery rate (FDR)  < 0.05]. Following adjustment for genomic control (λ = 1.462), no DMPs remained epigenome-wide significant (FDR < 0.05). This hypothesis-generating study found that fathers’ smoking was associated with differential methylation in their adolescent and adult offspring. Future studies are needed to explore the intriguing hypothesis that fathers’ exposures might persistently modify their future offspring’s epigenome