DNA methylation in the placenta and household 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 household-level indicators of Socioeconomic Position, Financial Resources, and/or Disadvantage. We additionally tested for associations with DNAme-derived epivariables of inferred cell composition and epigenetic age acceleration. 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; no CpGs were associated with Resources or Disadvantage. We also examined a less stringent |∆β|> 0.02 threshold (the lower limit of technical detection in this cohort) to ensure we were not missing small-effect SES associations. At this threshold there were 77 and 22 CpGs associated with Socioeconomic Position and Disadvantage, respectively, although closer inspection revealed that these changes were strongly associated with Hispanic ethnicity, and were likely explained by unaccounted for genetic variation in this cohort. In epivariable analyses, higher values of the Resources composite were associated with decreased cytotrophoblast:syncytiotrophoblast ratios in XY placentas only; this ratio is a novel metric that may reflect patterns of placental maturation and decreases over toward term in normative pregnancies. No SES metrics were associated with epigenetic age acceleration. CONCLUSIONS: In this diverse pregnancy cohort, we found little evidence that SES measures were associated with widespread alterations in placental DNAme. Importantly, DNAme-SES associations observed prior to adjustment for genetic ancestry were attenuated after ancestry-informed modeling, highlighting the potential for confounding in epigenetic studies of social exposures, particularly in heterogeneous cohorts. Our findings underscore the importance of carefully accounting for ancestry-related variation in DNAme studies, and will inform the design of future studies aimed at investigating the molecular correlates of socioeconomic disparities in pregnancy and early life, and the associated adverse birth and developmental outcomes.