Placental epigenetic clocks: estimating gestational age using placental DNA methylation levels

• Type of Material: Article
• Authors: Yungsung Lee, Norwegian Institute of Public Health; Sanaa Choufani, The Hospital for Sick Children; Rosanna Weksberg, University of Toronto; Samantha L. Wilson, University of British Columbia; Victor Yuan, University of British Columbia; Amber Burt, Emory University; Carmen Marsit, Emory University; Ake T. Lu, University of California Los Angeles; Beate Ritz, University of California Los Angeles; Jon Bohlin, Norwegian Institute of Public Health; Hakon K. Gjessing, Norwegian Institute of Public Health; Jennifer R. Harris, Norwegian Institute of Public Health; Per Magnus, Norwegian Institute of Public Health; Alexandra M. Binder, Norwegian Institute of Public Health; Wendy P. Robinson, University of British Columbia; Astanand Jugessur, Norwegian Institute of Public Health; Steve Horvath, University of California Los Angeles
• Language: English
• Date: 2019-06-30
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © Lee et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/aging.102049
• Title of Journal or Parent Work: Aging
• ISSN: 1945-4589
• Volume: 11
• Issue: 12
• Start Page: 4238
• End Page: 4253
• Grant/Funding Information: The work of VY and WPR was supported by the National Institutes of Health (to WPR; RFN 5R01HD089713-04).; Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number K07CA225856 (to AMB).; SH acknowledges support from the National Institutes of Health (NIH) (1U01AG060908 – 01).; The work of JB, HKG, JRH, PM, AJ was supported by the Research Council of Norway Center of Excellence funding scheme (Grant 262700).; This work is partly supported by a grant from the Norwegian Research Council (NRC) to AJ (project number 262043) and additional funding to YL from the NRC through a Personal Overseas Research Grant (project number 262043/F20).
• Keywords: Cell Biology; placenta; EPIGENOME-WIDE; epigenetic clock; Life Sciences & Biomedicine; MATERNAL PLASMA; TERM NEWBORNS; REGULARIZATION; QUANTILE NORMALIZATION; Science & Technology; PREECLAMPSIA; GENE-EXPRESSION; HYPOMETHYLATION; FETAL BIPARIETAL DIAMETER; DNA methylation; LATE-PRETERM; Geriatrics & Gerontology; gestational age
• Research Categories: Biology, Cell; Biology, Biostatistics; Biology, Genetics

Abstract

The human pan-tissue epigenetic clock is widely used for estimating age across the entire lifespan, but it does not lend itself well to estimating gestational age (GA) based on placental DNAm methylation (DNAm) data. We replicate previous findings demonstrating a strong correlation between GA and genome-wide DNAm changes. Using substantially more DNAm arrays (n=1,102 in the training set) than a previous study, we present three new placental epigenetic clocks: 1) a robust placental clock (RPC) which is unaffected by common pregnancy complications (e.g., gestational diabetes, preeclampsia), 2) a control placental clock (CPC) constructed using placental samples from pregnancies without known placental pathology, and 3) a refined RPC for uncomplicated term pregnancies. These placental clocks are highly accurate estimators of GA based on placental tissue; e.g., predicted GA based on RPC is highly correlated with actual GA (r > 0.95 in test data, median error less than one week). We show that epigenetic clocks derived from cord blood or other tissues do not accurately estimate GA in placental samples. While fundamentally different from Horvath's pan-tissue epigenetic clock, placental clocks closely track fetal age during development and may have interesting applications.