Dataset Information

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium.

ABSTRACT: Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10-7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.

SUBMITTER: Sharp GC

PROVIDER: S-EPMC5656174 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium.

Sharp Gemma C GC Salas Lucas A LA Monnereau Claire C Allard Catherine C Yousefi Paul P Everson Todd M TM Bohlin Jon J Xu Zongli Z Huang Rae-Chi RC Reese Sarah E SE Xu Cheng-Jian CJ Baïz Nour N Hoyo Cathrine C Agha Golareh G Roy Ritu R Holloway John W JW Ghantous Akram A Merid Simon K SK Bakulski Kelly M KM Küpers Leanne K LK Zhang Hongmei H Richmond Rebecca C RC Page Christian M CM Duijts Liesbeth L Lie Rolv T RT Melton Phillip E PE Vonk Judith M JM Nohr Ellen A EA Williams-DeVane ClarLynda C Huen Karen K Rifas-Shiman Sheryl L SL Ruiz-Arenas Carlos C Gonseth Semira S Rezwan Faisal I FI Herceg Zdenko Z Ekström Sandra S Croen Lisa L Falahi Fahimeh F Perron Patrice P Karagas Margaret R MR Quraishi Bilal M BM Suderman Matthew M Magnus Maria C MC Jaddoe Vincent W V VWV Taylor Jack A JA Anderson Denise D Zhao Shanshan S Smit Henriette A HA Josey Michele J MJ Bradman Asa A Baccarelli Andrea A AA Bustamante Mariona M Håberg Siri E SE Pershagen Göran G Hertz-Picciotto Irva I Newschaffer Craig C Corpeleijn Eva E Bouchard Luigi L Lawlor Debbie A DA Maguire Rachel L RL Barcellos Lisa F LF Davey Smith George G Eskenazi Brenda B Karmaus Wilfried W Marsit Carmen J CJ Hivert Marie-France MF Snieder Harold H Fallin M Daniele MD Melén Erik E Munthe-Kaas Monica C MC Arshad Hasan H Wiemels Joseph L JL Annesi-Maesano Isabella I Vrijheid Martine M Oken Emily E Holland Nina N Murphy Susan K SK Sørensen Thorkild I A TIA Koppelman Gerard H GH Newnham John P JP Wilcox Allen J AJ Nystad Wenche W London Stephanie J SJ Felix Janine F JF Relton Caroline L CL

Human molecular genetics 20171001 20

Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the ef ...[more]

PMID: 29016858

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Project description:BackgroundMaternal pre-pregnancy obesity is an established risk factor for childhood obesity. Investigating epigenetic alterations induced by maternal obesity during fetal development could gain mechanistic insight into the developmental origins of childhood obesity. While obesity disproportionately affects underrepresented racial and ethnic mothers and children in the USA, few studies investigated the role of prenatal epigenetic programming in intergenerational obesity of these high-risk populations.MethodsThis study included 903 mother-child pairs from the Boston Birth Cohort, a predominantly urban, low-income minority birth cohort. Mother-infant dyads were enrolled at birth and the children were followed prospectively to age 18 years. Infinium Methylation EPIC BeadChip was used to measure epigenome-wide methylation level of cord blood. We performed an epigenome-wide association study of maternal pre-pregnancy body mass index (BMI) and cord blood DNA methylation (DNAm). To quantify the degree to which cord blood DNAm mediates the maternal BMI-childhood obesity, we further investigated whether maternal BMI-associated DNAm sites impact birthweight or childhood overweight or obesity (OWO) from age 1 to age 18 and performed corresponding mediation analyses.ResultsThe study sample contained 52.8% maternal pre-pregnancy OWO and 63.2% offspring OWO at age 1-18 years. Maternal BMI was associated with cord blood DNAm at 8 CpG sites (genome-wide false discovery rate [FDR] < 0.05). After accounting for the possible interplay of maternal BMI and smoking, 481 CpG sites were discovered for association with maternal BMI. Among them 123 CpGs were associated with childhood OWO, ranging from 42% decrease to 87% increase in OWO risk for each SD increase in DNAm. A total of 14 identified CpG sites showed a significant mediation effect on the maternal BMI-child OWO association (FDR < 0.05), with mediating proportion ranging from 3.99% to 25.21%. Several of these 14 CpGs were mapped to genes in association with energy balance and metabolism (AKAP7) and adulthood metabolic syndrome (CAMK2B).ConclusionsThis prospective birth cohort study in a high-risk yet understudied US population found that maternal pre-pregnancy OWO significantly altered DNAm in newborn cord blood and provided suggestive evidence of epigenetic involvement in the intergenerational risk of obesity.

Dataset Information

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium.

Publications

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium.

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