Placental Gene Transcription and Child Cognitive and Behavioral Outcomes

Abstract

Background/Aim: The placenta plays an important role in neurodevelopment by synthesizing key hormones and providing nutrients involved in brain development. To date, no study has examined child cognitive outcomes in the context of the placental transcriptome.Methods: Placental transcriptomic data for 637 mother-child dyads (327 girls; 310 boys) from the CANDLE study (ECHO/PATHWAYS consortium) were obtained using paired-end RNA sequencing. Genes (N=13321) were clustered using Weighted Gene Co-expression Network Analysis (WGCNA). Cluster eigenvectors (eigengenes) were used as explanatory variables for three different outcome measures from the 4-6-year visit: Stanford Binet-5 full scale intelligence quotient (FSIQ) and externalizing or internalizing score from the Child Behavior Checklist (CBCL). Associations between outcomes and eigengenes were modeled in separate regressions controlling for covariates, adjusting p-values using Benjamini-Hochberg FDR correction (significance cutoff = 0.05). Separate analyses in sex-stratified datasets examined effect modification by sex. Functions of gene clusters were inferred using Fisher’s exact test based on Gene Ontology terms (unadjusted p-value cutoff = 0.0001).Results: Overall, two clusters (macromolecule metabolism and cell membrane structure) were negatively associated with FSIQ. Four clusters (nuclear protein transport, mitochondrial cristae, angiogenesis, and ribosome structure) were positively associated with and one cluster (biomolecule location maintenance) was negatively associated with CBCL externalizing score. In girls, FSIQ was positively associated with one cluster (myeloid leukocyte activation). In boys, FSIQ was negatively associated with one cluster (protein modification) and positively associated with another cluster (macromolecule metabolism). CBCL externalizing score in boys was positively associated with one cluster (mitochondrial cristae). All associations became nonsignificant after p-value adjustment.Conclusion: In this first study to assess placental transcriptome relationships with childhood neurodevelopmental outcomes, we identified functional gene clusters involved in diverse biological pathways that may provide evidence for a mechanistic link between the placenta and child cognitive and behavioral outcomes that may differ by sex.