Placental genomics mediates genetic associations with complex health traits and disease

• Authors: Arjun Bhattacharya, University of California Los Angeles; Anastasia N Freedman, University of North Carolina; Vennela Avula, University of North Carolina; Rebeca Harris, University of North Carolina; Weifang Liu, University of North Carolina; Calvin Pan, University of California Los Angeles; Aldons J Lusis, University of California Los Angeles; Robert M Joseph, Boston University; Lisa Smeester, University of North Carolina; Hadley J Hartwell, University of North Carolina; Karl CK Kuban, Boston University; Carmen Marsit, Emory University; Yun Li, University of North Carolina; Michael T O'Shea, University of North Carolina; Rebecca C Fry, University of North Carolina; Hudson P Santos, University of North Carolina
• Journal Title: NATURE COMMUNICATIONS
• Volume: Volume 13, Number 1
• Publisher: NATURE PORTFOLIO | 2022-02-04, Pages 706-706
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s41467-022-28365-x
• Subjects: Health Sciences, Medicine and Surgery; Environmental Sciences; Health Sciences, Public Health
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; DNA METHYLATION; DIFFERENTIAL EXPRESSION; MENDELIAN RANDOMIZATION; WIDE ASSOCIATION; IMPRINTED GENES; FETAL-GROWTH; CELL-LINE; IDENTIFICATION; NORMALIZATION; EPIGENETICS

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<2.5×10−6, 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.