title: An epigenetic clock for gestational age at birth based on blood methylation data.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Genetics and Molecular Biology Program, Emory University, Atlanta, GA, USA.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Knight
authors.affiliation: Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Parkville, Victoria, 3052, Australia.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Craig
authors.affiliation: The Royal Women's Hospital, Murdoch Childrens Research Institute and University of Melbourne, Parkville, Victoria, 3052, Australia.
authors.forename: Christiane
authors.initials: C
authors.lastname: Theda
authors.affiliation: Section of Neonatal Genetics, Danish Centre for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Artillerivej 5, DK-2300, Copenhagen S, Denmark.
authors.forename: Marie
authors.initials: M
authors.lastname: Bækvad-Hansen
authors.affiliation: Section of Neonatal Genetics, Danish Centre for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Artillerivej 5, DK-2300, Copenhagen S, Denmark.
authors.forename: Jonas
authors.initials: J
authors.lastname: Bybjerg-Grauholm
authors.affiliation: Section of Neonatal Genetics, Danish Centre for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Artillerivej 5, DK-2300, Copenhagen S, Denmark.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Hansen
authors.affiliation: Section of Neonatal Genetics, Danish Centre for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Artillerivej 5, DK-2300, Copenhagen S, Denmark.|The Danish Neonatal Screening Biobank, Department for Congenital Disorders, Statens Serum Institut, Artillerivej 5, DK-2300, Copenhagen S, Denmark.
authors.forename: Mads V
authors.initials: MV
authors.lastname: Hollegaard
authors.affiliation: Section of Neonatal Genetics, Danish Centre for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Artillerivej 5, DK-2300, Copenhagen S, Denmark.|The Danish Neonatal Screening Biobank, Department for Congenital Disorders, Statens Serum Institut, Artillerivej 5, DK-2300, Copenhagen S, Denmark.
authors.forename: David M
authors.initials: DM
authors.lastname: Hougaard
authors.affiliation: National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Fuglesangs Allé 4, 8210, Aarhus V, Denmark.
authors.forename: Preben B
authors.initials: PB
authors.lastname: Mortensen
authors.affiliation: Institute of Biological Psychiatry, Sct. Hans Mental Health Center, Copenhagen Mental Health Services, iPSYCH - The Lundbeck Foundation's Initiative for Integrative Psychiatric Research, Boserupvej, DK-4000, Roskilde, Denmark.
authors.forename: Shantel M
authors.initials: SM
authors.lastname: Weinsheimer
authors.affiliation: Institute of Biological Psychiatry, Sct. Hans Mental Health Center, Copenhagen Mental Health Services, iPSYCH - The Lundbeck Foundation's Initiative for Integrative Psychiatric Research, Boserupvej, DK-4000, Roskilde, Denmark.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Werge
authors.affiliation: Department of Psychology, Emory University, Atlanta, GA, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Brennan
authors.affiliation: Genetics and Molecular Biology Program, Emory University, Atlanta, GA, USA.|Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.|Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cubells
authors.affiliation: Departments of Psychiatry & Behavioral Sciences and Obstetrics & Gynecology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: D Jeffrey
authors.initials: DJ
authors.lastname: Newport
authors.affiliation: Departments of Psychiatry & Behavioral Sciences, Pediatrics, and Obstetrics & Gynecology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Zachary N
authors.initials: ZN
authors.lastname: Stowe
authors.affiliation: Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Parkville, Victoria, 3052, Australia.|The Royal Women's Hospital, Murdoch Childrens Research Institute and University of Melbourne, Parkville, Victoria, 3052, Australia.
authors.forename: Jeanie L Y
authors.initials: JL
authors.lastname: Cheong
authors.affiliation: Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Parkville, Victoria, 3052, Australia.
authors.forename: Philippa
authors.initials: P
authors.lastname: Dalach
authors.affiliation: Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Parkville, Victoria, 3052, Australia.|The Royal Women's Hospital, Murdoch Childrens Research Institute and University of Melbourne, Parkville, Victoria, 3052, Australia.
authors.forename: Lex W
authors.initials: LW
authors.lastname: Doyle
authors.affiliation: Murdoch Childrens Research Institute and Department of Paediatrics, University of Melbourne, Parkville, Victoria, 3052, Australia.
authors.forename: Yuk J
authors.initials: YJ
authors.lastname: Loke
authors.affiliation: Laboratory of Environmental Precision Biosciences, Columbia University Mailman School of Public Health, New York, NY, USA.
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Baccarelli
authors.affiliation: Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Allan C
authors.initials: AC
authors.lastname: Just
authors.affiliation: Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Wright
authors.affiliation: Center for Nutrition and Health Research, National Institute of Public Health, Cuernavaca, Morelos, Mexico.
authors.forename: Mara M
authors.initials: MM
authors.lastname: Téllez-Rojo
authors.affiliation: Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Svensson
authors.affiliation: Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Letizia
authors.initials: L
authors.lastname: Trevisi
authors.affiliation: Genetics and Molecular Biology Program, Emory University, Atlanta, GA, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Kennedy
authors.affiliation: Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.|Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.affiliation: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Stella
authors.initials: S
authors.lastname: Iurato
authors.affiliation: Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Darina
authors.initials: D
authors.lastname: Czamara
authors.affiliation: Institute of Behavioral Sciences, University of Helsinki, 00014, Helsinki, Finland.
authors.forename: Katri
authors.initials: K
authors.lastname: Räikkönen
authors.affiliation: Institute of Behavioral Sciences, University of Helsinki, 00014, Helsinki, Finland.|Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.|Folkhälsan Research Centre, Helsinki, Finland.
authors.forename: Jari M T
authors.initials: JM
authors.lastname: Lahti
authors.affiliation: Institute of Behavioral Sciences, University of Helsinki, 00014, Helsinki, Finland.
authors.forename: Anu-Katriina
authors.initials: AK
authors.lastname: Pesonen
authors.affiliation: National Institute for Health and Welfare, Children's Hospital, Helsinki University Hospital, 00271, Helsinki, Finland.|University of Helsinki, 00029, Helsinki, Finland.|Department of Obstetrics and Gynecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Eero
authors.initials: E
authors.lastname: Kajantie
authors.affiliation: Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, 00014, Helsinki, Finland.
authors.forename: Pia M
authors.initials: PM
authors.lastname: Villa
authors.affiliation: Medical and Clinical Genetics, and Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, 00014, Helsinki, Finland.|Institute for Molecular Medicine Finland, University of Helsinki, 00014, Helsinki, Finland.
authors.forename: Hannele
authors.initials: H
authors.lastname: Laivuori
authors.affiliation: HUSLAB and Department of Clinical Chemistry, Helsinki University Central Hospital, 00014, Helsinki, Finland.
authors.forename: Esa
authors.initials: E
authors.lastname: Hämäläinen
authors.affiliation: Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, US.
authors.forename: Hea Jin
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, US.
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Bailey
authors.affiliation: Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Sasha E
authors.initials: SE
authors.lastname: Parets
authors.affiliation: Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, US.
authors.forename: Varun
authors.initials: V
authors.lastname: Kilaru
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX, US.
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Menon
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA, 90095, US.|Department of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA, 90095, US.
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
authors.affiliation: Department of Psychiatry, University of California, San Francisco, CA, US.|Department of Pediatrics, University of California, San Francisco, CA, US.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Bush
authors.affiliation: Department of Psychiatry, University of California, San Francisco, CA, US.
authors.forename: Kaja Z
authors.initials: KZ
authors.lastname: LeWinn
authors.affiliation: Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, US.
authors.forename: Frances A
authors.initials: FA
authors.lastname: Tylavsky
authors.affiliation: Genetics and Molecular Biology Program, Emory University, Atlanta, GA, USA.|Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Karen N
authors.initials: KN
authors.lastname: Conneely
authors.affiliation: Genetics and Molecular Biology Program, Emory University, Atlanta, GA, USA. alicia.smith@emory.edu.|Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA. alicia.smith@emory.edu.|Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, US. alicia.smith@emory.edu.
authors.forename: Alicia K
authors.identifier: 0000-0002-8537-5156
authors.initials: AK
authors.lastname: Smith
mesh_terms: D000328:Adult; D000375:Aging / Q000235:genetics*; D015415:Biomarkers / Q000097:blood*; D001724:Birth Weight; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D047109:Fetal Development / Q000235:genetics; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy
chemical_list: D015415:Biomarkers
keywords: Aging; Biomarker; Birthweight; Blood spot; Cord blood; DNA methylation; Developmental age; Epigenetic clock; Fetus; Medicaid; Preterm birth; Socioeconomic status