Placental genomics mediates genetic associations with complex health traits and disease

Abstract

As the master regulator in utero, the placenta is core to the Developmental Origins of Health and Disease (DOHaD) hypothesis but is historically understudied. To identify placental gene-trait associations (GTAs) across the life course, we perform distal mediator-enriched transcriptome-wide association studies (TWAS) for 40 traits, integrating placental multi-omics from the Extremely Low Gestational Age Newborn Study. At $$P \; < \; 2.5\times {10}^{-6}$$ P < 2.5 × 10 − 6 , we detect 248 GTAs, mostly for neonatal and metabolic traits, across 176 genes, enriched for cell growth and immunological pathways. In aggregate, genetic effects mediated by placental expression significantly explain 4 early-life traits but no later-in-life traits. 89 GTAs show significant mediation through distal genetic variants, identifying hypotheses for distal regulation of GTAs. Investigation of one hypothesis in human placenta-derived choriocarcinoma cells reveal that knockdown of mediator gene EPS15 upregulates predicted targets SPATA13 and FAM214A, both associated with waist-hip ratio in TWAS, and multiple genes involved in metabolic pathways. These results suggest profound health impacts of placental genomic regulation in developmental programming across the life course.

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 [ 70 , 111 , 127 ]. Impaired trophoblast differentiation and altered composition of these cell populations in the placenta are 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) [ 18 ]. 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.…”

Methylation status of VTRNA2-1/nc886 is stable across human populations, monozygotic twin pairs and in majority of somatic tissues

“…To analyse the methylation of nc886 across different tissues, 17 datasets were utilized. These included a dataset consisting of 30 tissues from a 112-year-old female (56), as well as datasets consisting of different brain regions ((57), GSE134379), adipose tissue (54,58), muscle (46,(55)(56)(57), GSE142141, GSE171140), liver (58), buccal swabs (52,61), skin (62), sperm (63,64) and placenta (65)(66)(67)(68). All utilized datasets are described in detail in Supplementary Table 1.…”

Methylation status of VTRNA2-1 / nc886 is stable across populations, monozygotic twin pairs and in majority of tissues

“…To analyze the methylation of nc886 across different tissues, 17 datasets were used. These included a dataset consisting of 30 tissues from a 112-year-old female [57], as well as datasets consisting of different brain regions [58] (GSE134379), adipose tissue [54,59], muscle [46,55,56,57,60], (GSE142141, GSE171140), liver [59], buccal swabs [52,62], skin [63], sperm [64,65] and placenta [66][67][68][69]. All datasets are described in detail in Supplementary Table 1.…”