Genetic control of fetal placental genomics contributes to development of health and disease

Abstract

As the master regulator of the intrauterine environment, the placenta is core to the Developmental Origins of Health and Disease (DOHaD) but is understudied in relation to tissue-specific gene and trait regulation. We performed distal mediator-enriched transcriptome-wide association studies (TWAS) for 40 health traits across 5 physiological categories, using gene expression models trained with multi-omic data from the Extremely Low Gestational Age Newborn Study (N = 272). At P < 2.5 × 10-6, we detected 248 gene-trait associations (GTAs) across 176 genes, mostly for metabolic and neonatal traits and enriched for cell growth and immunological pathways. Of these GTAs, 89 showed significant mediation through genetic variants distal to the gene, identifying potential targets for functional validation. Functional validation of a mediator gene (EPS15) in human placenta-derived JEG-3 trophoblasts resulted in increased expression of its predicted targets, SPATA13 and FAM214A, both associated with the trait of waist-hip ratio in TWAS. These results illustrate the profound health impacts of placental genetic and genomic regulation in developmental programming across the life course.

Distal gene regulation mediated by non-coding RNAs contributes to germline risk for breast and prostate cancer

“…One systematic approach to identifying potential trans-mechanisms of regulation is to use genetic variants as causal anchors. A prevailing thought is that distal expression quantitative trait loci (eQTLs) of genes, where the genetic variant is far away from the gene (more than 1 Megabase, or Mb), are often themselves local-, or cis-acting, QTLs of a regulatory feature [17][18][19][20][21][22] .…”

“…One systematic approach to identifying potential trans -mechanisms of regulation is to use genetic variants as causal anchors. A prevailing thought is that distal expression quantitative trait loci (eQTLs) of genes, where the genetic variant is far away from the gene (more than 1 Megabase, or Mb), are often themselves local-, or cis -acting, QTLs of a regulatory feature 17–22 . We emphasize that the modifiers “local” and “distal” refer merely to distances in the genome (i.e., within or outside 1 Mb), whereas cis - and trans -acting refer to the biological mechanism (i.e., direct or indirect interaction).…”

Early Human Trophoblast Development: From Morphology To Function

“…Differentiation into trophoblast subpopulations and acquisition of diverse phenotypes include molecular changes such as remodeling of the cytoskeletal composition and a switch of the adhesion molecule pattern, depending on spatiotemporal requirements of the respective cells [57,88,102]. Impaired trophoblast differentiation and altered composition of these cell populations in the placenta is associated with placental dysfunction and pregnancy complications that are suggested to give rise to aberrant fetal development and increased risk of long-term development of chronic diseases in the offspring later in life, in a concept known as the Fetal Origins Hypothesis or Developmental Origin of Health and Diseases (DOHaD) [16]. This review article focuses on what is known about very early processes in human reproduction and emphasizes on morphological and functional aspects of early trophoblast subpopulations.…”