Investigating transgenerational effects of maternal psychological distress through infant gene expression profiles in a south african birth cohort study

Psychological stressors are prevalent during pregnancy, particularly in low- and middle-income countries (LMICs). A number of studies have demonstrated that prenatal exposure to maternal psychological distress may alter the expression of placental and/or umbilical cord blood (UCB) genes. However, findings have thus far been inconsistent, and the molecular mechanisms underlying these transgenerational effects are currently not well understood. This study aimed to investigate these transgenerational mechanisms using child gene expression profiles, with data from the Drakenstein Child Health Study (DCHS) – an ongoing, longitudinal birth cohort study in South Africa. The Self-Reporting Questionnaire 20 (SRQ-20) was used as a measure of prenatal maternal psychological distress, and a cut-off score >/= 8 was used to dichotomise participants as “high-risk” versus “low-risk”. RNA sequencing of umbilical cord blood samples was performed, on newborns exposed to prenatal maternal psychological distress (N=38) and compared to unexposed newborns (N=195). The linear modelling frameworks of the Limma-Voom R-package were applied to identify differentially expressed genes (DEGs) between exposed versus unexposed neonates. Covariates in these analyses included sex of the newborn, gestational age, maternal (self-reported) ethnicity, maternal HIV status, maternal hypertension, maternal prenatal alcohol consumption, maternal prenatal smoking, batch number and RNA integrity number. Thereafter, a gene set enrichment analysis (GSEA) was undertaken to identify significantly enriched pathways. Data from 234 mother-child dyads were included in this analysis. At genome-wide FDR < 0.05, no genes were found to be significantly differentially expressed between newborns exposed to prenatal maternal psychological distress, versus unexposed newborns, after controlling for relevant covariates. However, GSEA (at a nominal p-value < 0.01) demonstrated significant upregulation of genes differentially expressed between exposed versus unexposed newborns, in a number of MSigDB gene set pathways - namely, a) G2M checkpoint, (b) E2F targets, (c) mitotic spindle, (d) MTORC1 signalling, (e) heme metabolism and (f) oestrogen response late. Taken together, the findings suggest that genes differentially expressed between newborns exposed to prenatal maternal psychological distress are significantly upregulated in pathways associated with cell cycle and growth, oestrogen response and heme metabolism. Thus, multiple biological processes may be disrupted by an unfavourable intrauterine environment. Future research to replicate these findings and investigate potential developmental sequelae of these molecular changes would be warranted.