@article{edb577dee3b04c64a7a456a38ae52165,
title = "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 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 (1kg/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 association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for a causal 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.",
keywords = "Body Mass Index, BMI, Adiposity, Epigenetics, Negative control, Causal inference, Prenatal, Epidemiology, Pregnancy",
author = "Sharp, {Gemma C} and {The Pregnancy and Childhood Epigenetics (PACE) consortium} and Salas, {Lucas A} and Claire Monnereau and Catherine Allard and Paul Yousefi and Everson, {Todd M} and Jon Bohlin and Zongli Xu and Rae-Chi Huang and Reese, {Sarah E} and Cheng-Jian Xu and Nour Ba{\"i}z and Cathrine Hoyo and Golareh Agha and Ritu Roy and Holloway, {John W} and Akram Ghantous and Merid, {Simon K} and Bakulski, {Kelly M} and K{\"u}pers, {Leanne K} and Hongmei Zhang and Richmond, {Rebecca C} and Page, {Christian M} and Liesbeth Duijts and Lie, {Rolv T} and Melton, {Phillip E} and Vonk, {Judith M} and Nohr, {Ellen A} and ClarLynda Williams-DeVane and Karen Huen and Rifas-Shiman, {Sheryl L} and Carlos Ruiz-Arenas and Semira Gonseth and Rezwan, {Faisal I} and Zdenko Herceg and Sandra Ekstr{\"o}m and Lisa Croen and Fahimeh Falahi and Patrice Perron and Karagas, {Margaret R} and Quraishi, {Bilal M} and Suderman, {Matthew J} and Magnus, {Maria C} and Jaddoe, {Vincent W V} and Taylor, {Jack A} and Denise Anderson and Lawlor, {Debbie A} and {Davey Smith}, George and S{\o}rensen, {Thorkild I A} and Relton, {Caroline L}",
year = "2017",
month = oct,
day = "15",
doi = "10.1093/hmg/ddx290",
language = "English",
volume = "26",
pages = "4067--4085",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "20",
}