title: Cell type specific DNA methylation in cord blood: A 450K-reference data set and cell count-based validation of estimated cell type composition.
abstract: Epigenome-wide association studies of prenatal exposure to different environmental factors are becoming increasingly common. These studies are usually performed in umbilical cord blood. Since blood comprises multiple cell types with specific DNA methylation patterns, confounding caused by cellular heterogeneity is a major concern. This can be adjusted for using reference data consisting of DNA methylation signatures in cell types isolated from blood. However, the most commonly used reference data set is based on blood samples from adult males and is not representative of the cell type composition in neonatal cord blood. The aim of this study was to generate a reference data set from cord blood to enable correct adjustment of the cell type composition in samples collected at birth. The purity of the isolated cell types was very high for all samples (>97.1%), and clustering analyses showed distinct grouping of the cell types according to hematopoietic lineage. We explored whether this cord blood and the adult peripheral blood reference data sets impact the estimation of cell type composition in cord blood samples from an independent birth cohort (MoBa, n = 1092). This revealed significant differences for all cell types. Importantly, comparison of the cell type estimates against matched cell counts both in the cord blood reference samples (n = 11) and in another independent birth cohort (Generation R, n = 195), demonstrated moderate to high correlation of the data. This is the first cord blood reference data set with a comprehensive examination of the downstream application of the data through validation of estimated cell types against matched cell counts.
authors: a Department of Medical Genetics , Oslo University Hospital , Oslo , Norway.
authors: Kristina
authors: K
authors: Gervin
authors: b Division of Mental and Physical Health , Norwegian Institute of Public Health , Oslo , Norway.
authors: Christian Magnus
authors: CM
authors: Page
authors: c Department of Medical Biochemistry , Oslo University Hospital , Oslo , Norway.
authors: Hans Christian D
authors: HC
authors: Aass
authors: d The Generation R Study Group, Erasmus MC , University Medical Center Rotterdam , the Netherlands.|e Department of Pediatrics, Erasmus MC , University Medical Center Rotterdam , the Netherlands.|f Department of Immunology, Erasmus MC , University Medical Center Rotterdam , the Netherlands.
authors: Michelle A
authors: MA
authors: Jansen
authors: g Departments of Obstetrics and Gynecology , Oslo University Hospital , Oslo , Norway.
authors: Heidi Elisabeth
authors: HE
authors: Fjeldstad
authors: h Cancer Registry of Norway , Institute of population based Cancer Research , Oslo , Norway.
authors: Bettina Kulle
authors: BK
authors: Andreassen
authors: d The Generation R Study Group, Erasmus MC , University Medical Center Rotterdam , the Netherlands.|i Department of Pediatrics, Division of Respiratory Medicine, Erasmus MC , University Medical Center Rotterdam , the Netherlands.|j Department of Pediatrics, Division of Neonatology, Erasmus MC , University Medical Center Rotterdam , the Netherlands.|k Department of Epidemiology, Erasmus MC , University Medical Center Rotterdam , the Netherlands.
authors: Liesbeth
authors: L
authors: Duijts
authors: l Department of Internal Medicine, Erasmus MC , University Medical Center Rotterdam , the Netherlands.
authors: Joyce B
authors: JB
authors: van Meurs
authors: m Department of Immunology, Erasmus MC , University Medical Center Rotterdam , the Netherlands.|n Department of Immunology and Pathology, Central Clinical School , Monash University , Melbourne , Victoria , Australia.
authors: Menno C
authors: MC
authors: van Zelm
authors: d The Generation R Study Group, Erasmus MC , University Medical Center Rotterdam , the Netherlands.|e Department of Pediatrics, Erasmus MC , University Medical Center Rotterdam , the Netherlands.|k Department of Epidemiology, Erasmus MC , University Medical Center Rotterdam , the Netherlands.
authors: Vincent W
authors: VW
authors: Jaddoe
authors: o Pharmacoepidemiology and Drug Safety Research Group, Department of Pharmacy, School of Pharmacy , University of Oslo , Norway.|p PharmaTox Strategic Research Initiative, Faculty of Mathematics and Natural Sciences , University of Oslo , Oslo , Norway.
authors: Hedvig
authors: H
authors: Nordeng
authors: q Health Data and Digitalisation , Norwegian Institute of Public Health , Oslo , Norway.
authors: Gunn Peggy
authors: GP
authors: Knudsen
authors: q Health Data and Digitalisation , Norwegian Institute of Public Health , Oslo , Norway.
authors: Per
authors: P
authors: Magnus
authors: b Division of Mental and Physical Health , Norwegian Institute of Public Health , Oslo , Norway.
authors: Wenche
authors: W
authors: Nystad
authors: g Departments of Obstetrics and Gynecology , Oslo University Hospital , Oslo , Norway.|r Faculty of Medicine , University of Oslo , Oslo , Norway.
authors: Anne Cathrine
authors: AC
authors: Staff
authors: d The Generation R Study Group, Erasmus MC , University Medical Center Rotterdam , the Netherlands.|e Department of Pediatrics, Erasmus MC , University Medical Center Rotterdam , the Netherlands.|k Department of Epidemiology, Erasmus MC , University Medical Center Rotterdam , the Netherlands.
authors: Janine F
authors: JF
authors: Felix
authors: a Department of Medical Genetics , Oslo University Hospital , Oslo , Norway.|o Pharmacoepidemiology and Drug Safety Research Group, Department of Pharmacy, School of Pharmacy , University of Oslo , Norway.|p PharmaTox Strategic Research Initiative, Faculty of Mathematics and Natural Sciences , University of Oslo , Oslo , Norway.
authors: Robert
authors: R
authors: Lyle
mesh_terms: D000328:Adult; D001773:Blood Cells / Q000145:classification / Q000166:cytology* / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D005312:Fetal Blood / Q000166:cytology*; D005434:Flow Cytometry / Q000592:standards*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D012015:Reference Standards
keywords: Cellular heterogeneity; DNA methylation; EWAS; cord blood; reference data set