Placental genomics mediates genetic associations with complex health traits and disease

• Type of Material: Article
• 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
• Language: English
• Date: 2022-02-04
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-022-28365-x
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 13
• Issue: 1
• Start Page: 706
• End Page: 706
• Grant/Funding Information: This study was supported by grants from the National Institutes of Health (NIH), specifically the National Institute of Neurological Disorders and Stroke (U01NS040069; R01NS040069), the Office of the NIH Director (UG3OD023348), the National Institute of Environmental Health Sciences (T32-ES007018; P30ES019776; R24ES028597), the National Heart, Lung and Blood Institute (R01HL47883, R01HL148577), the National Institute of Nursing Research (K23NR017898; R01NR019245), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD092374; R03HD101413; P50HD103573).
• Keywords: Multidisciplinary Sciences; IDENTIFICATION; IMPRINTED GENES; WIDE ASSOCIATION; NORMALIZATION; CELL-LINE; DIFFERENTIAL EXPRESSION; EPIGENETICS; Science & Technology - Other Topics; DNA METHYLATION; MENDELIAN RANDOMIZATION; Science & Technology; FETAL-GROWTH
• Research Categories: Environmental Sciences; Health Sciences, Public Health; Health Sciences, Medicine and Surgery

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.