Placental genomics mediates genetic associations with complex health traits and disease

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

doi:10.1038/s41467-022-28365-x

Placental genomics mediates genetic associations with complex health traits and disease

Nat Commun. 2022 Feb 4;13(1):706. doi: 10.1038/s41467-022-28365-x.

Authors

Arjun Bhattacharya^{1

2}, Anastasia N Freedman³, Vennela Avula³, Rebeca Harris⁴, Weifang Liu⁵, Calvin Pan⁶, Aldons J Lusis^{6

7

8}, Robert M Joseph⁹, Lisa Smeester^{3

10

11}, Hadley J Hartwell³, Karl C K Kuban¹², Carmen J Marsit¹³, Yun Li^{5

14

15}, T Michael O'Shea¹⁶, Rebecca C Fry^#^{17

18

19}, Hudson P Santos Jr^#^{20

21}

Affiliations

¹ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA. abtbhatt@ucla.edu.
² Institute for Quantitative and Computational Biosciences, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA. abtbhatt@ucla.edu.
³ Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27514, USA.
⁴ Biobehavioral Laboratory, School of Nursing, University of North Carolina, Chapel Hill, NC, 27514, USA.
⁵ Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27514, USA.
⁶ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
⁷ Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
⁸ Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
⁹ Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, 02118, USA.
¹⁰ Institute for Environmental Health Solutions, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27514, USA.
¹¹ Curriculum in Toxicology and Environmental Medicine, University of North Carolina, Chapel Hill, NC, 27514, USA.
¹² Department of Pediatrics, Division of Pediatric Neurology, Boston University Medical Center, Boston, MA, 02118, USA.
¹³ Gangarosa Department of Environmental Health, Rollins School of Public Health Emory University, Atlanta, GA, 30322, USA.
¹⁴ Department of Genetics, University of North Carolina, Chapel Hill, NC, 27514, USA.
¹⁵ Department of Computer Science, University of North Carolina, Chapel Hill, NC, 27514, USA.
¹⁶ Department of Pediatrics, School of Medicine, University of North Carolina, Chapel Hill, NC, 27514, USA.
¹⁷ Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27514, USA. rfry@email.unc.edu.
¹⁸ Institute for Environmental Health Solutions, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27514, USA. rfry@email.unc.edu.
¹⁹ Curriculum in Toxicology and Environmental Medicine, University of North Carolina, Chapel Hill, NC, 27514, USA. rfry@email.unc.edu.
²⁰ Biobehavioral Laboratory, School of Nursing, University of North Carolina, Chapel Hill, NC, 27514, USA. hsantosj@email.unc.edu.
²¹ Institute for Environmental Health Solutions, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27514, USA. hsantosj@email.unc.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural

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*

Substances

Adaptor Proteins, Signal Transducing
EPS15 protein, human
Guanine Nucleotide Exchange Factors
SPATA13 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding