An epigenetic clock for gestational age at birth based on blood methylation data

• Type of Material: Article
• Authors: Anna K. Knight, Emory University; Jeffrey M. Craig, University of Melbourne; Christiane Theda, Royal Women’s Hospital; Marie Bækvad-Hansen, Statens Serum Institut; Jonas Bybjerg-Grauholm, Statens Serum Institut; Christine S. Hansen, Statens Serum Institut; Mads V. Hollegaard, Statens Serum Institut; David M. Hougaard, Statens Serum Institut; Preben B. Mortensen, Aarhus University; Shantel M. Weinsheimer, Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH); Thomas M. Werge, Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH); Patricia Brennan, Emory University; Joseph Cubells, Emory University; D. Jeffrey Newport, University of Miami; Zachary N. Stowe, University of Arkansas for Medical Sciences; Jeanie L.Y. Cheong, University of Melbourne; Philippa Dalach, University of Melbourne; Lex W. Doyle, University of Melbourne; Yuk J. Loke, University of Melbourne; Andrea A. Baccarelli, Columbia University; Allan C. Just, Icahn School of Medicine at Mount Sinai; Robert O. Wright, Icahn School of Medicine at Mount Sinai; Mara M. Tellez-Rojo, National Institute of Public Health, Mexico; Katherine Svensson, Icahn School of Medicine at Mount Sinai; Letizia Trevisi, Harvard University; Elizabeth M. Kennedy, Emory University; Elisabeth B. Binder, Emory University; Stella Iurato, Max Planck Institute of Psychiatry; Darina Czamara, Max Planck Institute of Psychiatry; Katri Räikkönen, University of Helsinki; Jari M.T. Lahti, University of Helsinki; Anu-Katriina Pesonen, University of Helsinki; Eero Kajantie, Helsinki University Hospital; Pia M. Villa, University of Helsinki; Hannele Laivuori, University of Helsinki; Esa Hämäläinen, University of Helsinki; Hea Jin Park, Emory University; Lynn B. Bailey, Emory University; Sasha E. Parets, Emory University; Varun Kilaru, Emory University; Ramkumar Menon, University of Texas Medical Branch; Steve Horvath, University of California Los Angeles; Nicole R. Bush, University of California San Francisco; Kaja Z. LeWinn, University of California San Francisco; Frances A. Tylavsky, University of Tennessee; Karen Conneely, Emory University; Alicia K Smith, Emory University
• Language: English
• Date: 2016-10-07
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2016 The Author(s). The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13059-016-1068-z
• Title of Journal or Parent Work: Genome Biology
• ISSN: 1465-6906
• Volume: 17
• Issue: 1
• Start Page: 206
• End Page: 206
• Grant/Funding Information: This research was supported by grants from the National Institutes of Minority and Health Disparities (R01MD009064 to AKS), the National Health and Medical Research Council of Australia (project grants 1083779, 491246; Centre of Research Excellence Grants 546519, 1060733, early career fellowship to JLYC 1053787), and the Urban Child Institute.; The PROGRESS/ELEMENT study was supported by funding from the National Institute of Environmental Health Sciences (R01ES020268; R01ES021357) and by the National Institute of Public Health/Ministry of Health of Mexico. The American British Cowdray Hospital provided facilities used for PROGRESS/ELEMENT research.; The FAP study was supported by the Georgia Experimental Agriculture Station, HATCH #GEO00706 and the Interdisciplinary Proposal Developmental Program at the University of Georgia.; Salary support for AKK, EMK, and SEP was provided, in part, by the National Institute of General Medical Sciences (T32GM008490) and the National Institute of Environmental Health Sciences (T32ES012870), respectively. Salary support for ACJ was provided by NIEHS grant K99 ES023450. Salary support for SH was provided by NIH/NIA 1U34AG051425-01.; WMHP sample collection was supported by the Translational Research Center in Behavioral Sciences (TRCBS; P50 MH077928 to ZNS) and methylation assays were provided by the National Institute of Mental Health (RC1 MH088609 to AKS/PAB).; Support for PREDO was provided by the Academy of Finland (grants 127437, 129306, 130326, 134791, and 263924), Sigrid Juselius Foundation, Foundation for Pediatric Research, Novo Nordisk Foundation (to EK). Additional support provided by the Academy of Finland grants 121196 and 134791, Finnish Medical Society Duodecim, Government Special Subsidy for Health Sciences at Helsinki and Uusimaa Hospital District, Jane and Aatos Erkko Foundation, Päivikki and Sakari Sohlberg Foundation, and University of Helsinki Research Funds (to HL).
• Keywords: Science & Technology; Blood spot; Fetus; PERCENTILE; WEIGHT; Aging; Life Sciences & Biomedicine; Medicaid; BRAIN-DEVELOPMENT; COHORT; Epigenetic clock; LATE-PRETERM; Biomarker; TERM NEWBORNS; CELL-TYPES; MORTALITY; Socioeconomic status; Pediatrics; Cord blood; Preterm birth; Developmental age; DNA methylation; Birthweight
• Research Categories: Biology, Genetics; Health Sciences, General; Health Sciences, Obstetrics and Gynecology

Abstract

Background: Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth. Results: We find that gestational age can be accurately estimated from DNA methylation of neonatal cord blood and blood spot samples. We calculate a DNA methylation gestational age using 148 CpG sites selected through elastic net regression in six training datasets. We evaluate predictive accuracy in nine testing datasets and find that the accuracy of the DNA methylation gestational age is consistent with that of gestational age estimates based on established methods, such as ultrasound. We also find that an increased DNA methylation gestational age relative to clinical gestational age is associated with birthweight independent of gestational age, sex, and ancestry. Conclusions: DNA methylation can be used to accurately estimate gestational age at or near birth and may provide additional information relevant to developmental stage. Further studies of this predictor are warranted to determine its utility in clinical settings and for research purposes. When clinical estimates are available this measure may increase accuracy in the testing of hypotheses related to developmental age and other early life circumstances.