DNA Methylation in the Placenta and Maternal Socioeconomic Status: The SPAH Study

Background: Disparities in socioeconomic status have been associated with adverse pregnancy outcomes, including preterm birth and fetal growth restriction. As the barrier between maternal exposures and the fetus, the placenta has been proposed to play a role in the mechanisms leading to poor health outcomes seen with socioeconomic disadvantage. We hypothesized that exposure to lower SES during pregnancy may lead to altered placental DNA methylation (DNAme) that is in turn associated with other pregnancy outcomes. Methods: Placental samples from the Stress, Pregnancy, and Health Study (SPAH) study (n=493) were processed for DNAme analysis using the Illumina Infinium MethylationEPIC BeadChip array. Linear modelling was used to assess whether placental DNAme was associated with Socioeconomic Position, Financial Resources, and/or Disadvantage. Results: At FDR <0.05 and |∆β| >0.05, we observed only 2 CpGs associated with Socioeconomic Position after correcting for gestational age and ancestry, while at a less stringent |∆β| >0.02 threshold there were 77 and 22 CpG associations with Socioeconomic Position and Disadvantage respectively. However, these changes seemed to be explained by genetic variation influencing DNAme in combination with population stratification by socioeconomic status. We did observe associations between socioeconomic status and DNAme-inferred cell composition and epigenetic age acceleration, with intrinsic (p=0.047) and extrinsic (p=0.050) age acceleration being slightly accelerated with lower levels of Socioeconomic Position. Financial Resources and Disadvantage SES trended in the same direction as Social Position, with lower socioeconomic status seen with higher levels of age acceleration, though not reaching significance. No meaningful associations in sex stratified analyses were identified, although XX placentas showed higher cytotrophoblast:syncytiotrophoblast ratio than XY placentas (p=0.00013). Conclusions: Our results emphasize the importance in placental studies involving diverse cohorts to account for genetic variation in order to avoid false findings. This study also demonstrates the challenges with elucidating mechanisms underlying socioeconomic associated outcomes, given the complex nature of correlated variables. Further investigation is required to elucidate whether epigenetic age acceleration is an adverse effect of exposure to prenatal maternal stress associated with socioeconomic disparities, or alternatively, if placental epigenetic aging is a potential healthy adaption to pregnancy complications that increase the risk of preterm delivery.