Placental gene co-expression networks and mediation analysis identifies pathways and genes associated with birthweight

The Developmental Origin of Health and Disease (DOHaD) concept postulates that birthweight (BW), a proxy of the in utero environment shaped by environmental and genetic factors, can impact future health. The placenta plays a key role in fetal growth and metabolic programming, thus essential to BW. However, the mechanisms by which intrauterine environment shapes BW, potentially via placenta, remain largely unknown. To investigate the placental contribution to BW, we profiled the placental transcriptome from two large U.S. birth cohorts. We constructed weighted gene co-expression networks (WGCN) from all (N=673), female (N=331) and male (N=342) placentae, and identified 23, 24, and 22 modules, respectively. Pathway enrichment analyses of these networks revealed consistent functional processes related to signal transduction, lysosomes, brain development, immune, and HIF-1 hypoxia pathways. Seven modules were associated with BW in each network, and differential expression analysis within these modules identified 441, 467 and 227 genes in the overall, female, and male networks, respectively. We also identified 14, 12, and 8 genes mediating the impact of WGCN modules on BW, including genes related to oxidative stress (SLC25A27, MCTP1 and CD9), brain development (NFIA and SEMA3D) and maternal-fetal immune tolerance (TLR1 and TLR6). Together, these placenta WGCNs revealed pathways and genes mediating the effect of placental transcriptome on BW offering mechanistic insights, including sex-specific mechanisms, on fetal programing. These findings support DOHaD and improve the understanding of how the intrauterine environment influences BW and later-life traits.