A Co-expression Analysis of the Placental Transcriptome in Association With Maternal Pre-pregnancy BMI and Newborn Birth Weight

Maternal body mass index (BMI) before pregnancy is known to affect both fetal growth and later-life health of the newborn, yet the implicated molecular mechanisms remain largely unknown. As the master regulator of the fetal environment, the placenta is a valuable resource for the investigation of processes involved in the developmental programming of metabolic health. We conducted a genome-wide placental transcriptome study aiming at the identification of functional pathways representing the molecular link between maternal BMI and fetal growth. We used RNA microarray (Agilent 8 x 60 K), medical records, and questionnaire data from 183 mother-newborn pairs from the ENVIRONAGE birth cohort study (Flanders, Belgium). Using a weighted gene co-expression network analysis, we identified 17 correlated gene modules. Three of these modules were associated with both maternal pre-pregnancy BMI and newborn birth weight. A gene cluster enriched for genes involved in immune response and myeloid cell differentiation was positively associated with maternal BMI and negatively with low birth weight. Two other gene modules, upregulated in association with maternal BMI as well as birth weight, were involved in processes related to organ and tissue development, with blood vessel morphogenesis and extracellular matrix structure as top Gene Ontology terms. In line with this, erythrocyte-, angiogenesis-, and extracellular matrix-related genes were among the identified hub genes. The association between maternal BMI and newborn weight was significantly mediated by gene expression for 5 of the hub genes (FZD4, COL15A1, GPR124, COL6A1, and COL1A1). As some of the identified hub genes have been linked to obesity in adults, our observation in placental tissue suggests that biological processes may be affected from prenatal life onwards, thereby identifying new molecular processes linking maternal BMI and fetal metabolic programming.