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Placental DNA methylation as mediators of assisted reproduction and parental metabolic risk on offspring phenotype: a multiethnic cohort study

ABSTRACT: Alterations in genomic imprinting are posited as a mechanism for effects of assisted reproduction technologies (ART) and in vitro fertilization (IVF) on long term offspring phenotype. Our previous work has investigated the role of fetal cord tissue DNA methylation in mediating these relationships (Huang, et al. 2021. DOI: 10.1038/s41467-021-25899-4). To study the extent to which fetal-derived placental DNA methylation may mediate these relationships, we conducted a nested cohort study within the Growing Up in Singapore Towards healthy Outcomes (GUSTO) prospective parent-offspring study. We assayed DNA methylation in 408 bulk placental tissue samples arising from 200 placenta obtained at the time of live singleton birth. We oversampled on the basis of conceptions via IVF (ART group) and spontaneous conceptions amongst couples where the father had one or more cardiometabolic risk factors (advanced age, obesity, hypertension, or diabetes history; SC_HIGHRISK group). We then took a random sample of all other spontaneous conceptions (SC_RANDOM). For each of 200 placentas, one sample each was taken from the fetal-facing and maternal facing side of the (fetal-derived) placenta. An additional 8 technical replicated were assayed resulted in the 408 total samples. After QC and elimination of replicates, DNA methylation data were available from 196 unique fetal-facing and 195 maternal-facing placental bulk tissue samples. These repeated measures were used to reduce residual technical and unmeasured confounding biases in downstream analyses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE208529 | GEO | 2022/08/01

REPOSITORIES: GEO

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Project description:OBJECTIVE: To determine whether deoxyribonucleic acid (DNA) methylation alterations exist in the first trimester human placenta between conceptions using fertility treatments and those that do not and, if so, whether differences are the result of underlying infertility or fertility treatments. We also assessed whether significant alterations led to changes in gene expression using bulk total RNA-seq from the same cohort (see Lee et al 2019, PMID: 30611556, NCBI GEO GSE215421). DESIGN: We compared DNA methylation of the first trimester placenta from singleton pregnancies that resulted in live births from unassisted, in vitro fertilization (IVF), and non-IVF fertility treatment (NIFT) conceptions using the Infinium MethylationEPIC BeadChip array. Differentially methylated probes (DMPs) were identified using a generalized linear model adjusted for fetal sex. Associated genes for significant CpG sites were cross-references in RNA-seq results to determine whether methylation alterations lead to differences in gene expression. SETTING: Academic medical center. PATIENTS: A total of 138 singleton pregnancies undergoing chorionic villus sampling resulting in a live birth were recruited for methylation analysis (56 unassisted, 38 NIFT, and 44 IVF conceptions). INTERVENTIONS AND TREATMENTS: In vitro fertilization-conceived pregnancy or pregnancy conceived via NIFT, such as ovulation induction and intrauterine insemination. RESULTS: Of the 741,145 CpG probes analyzed in the placenta, few were significant at Bonferroni <0.05: 185 CpG sites (0.025%) significant in pregnancies conceived with the fertility treatments (NIFT + IVF) versus unassisted conceptions; 28 in NIFT versus unassisted; 195 in IVF versus unassisted; and only 13 (0.0018%) in IVF versus NIFT conceptions. CONCLUSION: Underlying infertility is the most significant contributor to the minimal differences in first trimester placental methylation, and not the specific fertility treatment used, such as IVF.