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Maternal pre-pregnancy obesity, offspring cord blood DNA methylation, and offspring cardiometabolic health in early childhood: an epigenome-wide association study

posted on 2023-01-18, 14:00 authored by Chantel L. Martin, Dereje Jima, Gemma C. Sharp, Lauren E. McCullough, Sarah S. Park, Kymberly M. Gowdy, David Skaar, Michael Cowley, Rachel L. Maguire, Bernard Fuemmeler, David Collier, Caroline L. Relton, Susan K. Murphy, Cathrine Hoyo

Pre-pregnancy obesity is an established risk factor for adverse sex-specific cardiometabolic health in offspring. Epigenetic alterations, such as in DNA methylation (DNAm), are a hypothesized link; however, sex-specific epigenomic targets remain unclear. Leveraging data from the Newborn Epigenetics Study (NEST) cohort, linear regression models were used to identify CpG sites in cord blood leukocytes associated with pre-pregnancy obesity in 187 mother-female and 173 mother-male offsprings. DNAm in cord blood was measured using the Illumina HumanMethylation450k BeadChip. Replication analysis was conducted among the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Associations between pre-pregnancy obesity-associated CpG sites and offspring BMI z-score (BMIz) and blood pressure (BP) percentiles at 4–5-years of age were also examined. Maternal pre-pregnacy obesity was associated with 876 CpGs in female and 293 CpGs in male offspring (false discovery rate <5%). Among female offspring, 57 CpG sites, including the top 18, mapped to the TAPBP gene (range of effect estimates: −0.83% decrease to 4.02% increase in methylation). CpG methylation differences in the TAPBP gene were also observed among males (range of effect estimates: −0.30% decrease to 2.59% increase in methylation). While technically validated, none of the TAPBP CpG sites were replicated in ALSPAC. In NEST, methylation differences at CpG sites of the TAPBP gene were associated with BMI z-score (cg23922433 and cg17621507) and systolic BP percentile (cg06230948) in female and systolic (cg06230948) and diastolic (cg03780271) BP percentile in male offspring. Together, these findings suggest sex-specific effects, which, if causal, may explain observed sex-specific effects of maternal obesity.


The NEST project was conducted and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK: R01DK085173) and National Institute of Aging (NIA: R21AG041048) in collaboration with NEST investigators. This work was also funded by the National Institute of Environmental Health Sciences (grant number T32ES007018) and the National Institute for Minority Health and Health Disparities (grant number K99MD012808).. The UK Medical Research Council and Wellcome (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 GCS will serve as a guarantor for the contents of this paper. ALSPAC methylation data was generated through grants from the British Biological Sciences Research Council (BB/I025751/1 and BB/I025263/1). GCS and CLR work at the MRC Integrative Epidemiology Unit at the University of Bristol (grant numbers MC_UU_12013/2). The Bioinformatics analysis was supported in part by NIEHS under award number P30ES025128. The funders have no role in the research question, study design, data collection, statistical analysis, or preparation of the manuscript;National Institute of Environmental Health Sciences [T32ES007018];National Institute of Environmental Health Sciences [P30ES025128];National Institute on Aging [R21AG041048];National Institute on Minority Health and Health Disparities [K99MD012808];MRC Integrative Epidemiology Unit, The UK Medical Research Council and Wellcome [102215/2/13/2];University of Bristol [MC_UU_12013_1, MC_UU_12013_2].