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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Placental genomics mediates genetic associations with complex health traits and disease.

Authors: Bhattacharya, Arjun; Freedman, Anastasia N; Avula, Vennela; Harris, Rebeca; Liu, Weifang; Pan, Calvin; Lusis, Aldons J; Joseph, Robert M; Smeester, Lisa; Hartwell, Hadley J; Kuban, Karl C K; Marsit, Carmen J; Li, Yun; O'Shea, T Michael; Fry, Rebecca C; Santos Jr, Hudson P

Published In Nat Commun, (2022 Feb 04)

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 [Formula: see text], 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.

PubMed ID: 35121757 Exiting the NIEHS site

MeSH Terms: Adaptor Proteins, Signal Transducing/genetics; Animals; Disease/genetics*; Female; Genetic Association Studies/methods*; Genetic Predisposition to Disease/genetics; Genome-Wide Association Study/methods*; Genomics/methods*; Guanine Nucleotide Exchange Factors/genetics; Humans; Infant, Newborn; Mice; Multifactorial Inheritance/genetics*; Placenta/metabolism*; Pregnancy; Quantitative Trait Loci/genetics; RNA-Seq/methods; Transcriptome/genetics*

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