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

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.

Abbreviation
Hum. Mol. Genet.
Publication Date
2017-10-15
Volume
26
Issue
20
Page Numbers
4067-4085
Pubmed ID
29016858
Medium
Print
Full Title
Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium.
Authors
Sharp GC, Salas LA, Monnereau C, Allard C, Yousefi P, Everson TM, Bohlin J, Xu Z, Huang RC, Reese SE, Xu CJ, Baïz N, Hoyo C, Agha G, Roy R, Holloway JW, Ghantous A, Merid SK, Bakulski KM, Küpers LK, Zhang H, Richmond RC, Page CM, Duijts L, Lie RT, Melton PE, Vonk JM, Nohr EA, Williams-DeVane C, Huen K, Rifas-Shiman SL, Ruiz-Arenas C, Gonseth S, Rezwan FI, Herceg Z, Ekström S, Croen L, Falahi F, Perron P, Karagas MR, Quraishi BM, Suderman M, Magnus MC, Jaddoe VWV, Taylor JA, Anderson D, Zhao S, Smit HA, Josey MJ, Bradman A, Baccarelli AA, Bustamante M, Håberg SE, Pershagen G, Hertz-Picciotto I, Newschaffer C, Corpeleijn E, Bouchard L, Lawlor DA, Maguire RL, Barcellos LF, Davey Smith G, Eskenazi B, Karmaus W, Marsit CJ, Hivert MF, Snieder H, Fallin MD, Melén E, Munthe-Kaas MC, Arshad H, Wiemels JL, Annesi-Maesano I, Vrijheid M, Oken E, Holland N, Murphy SK, Sørensen TIA, Koppelman GH, Newnham JP, Wilcox AJ, Nystad W, London SJ, Felix JF, Relton CL