title: Enlarged leukocyte referent libraries can explain additional variance in blood-based epigenome-wide association studies.
abstract: We examined whether variation in blood-based epigenome-wide association studies could be more completely explained by augmenting existing reference DNA methylation libraries.
  
  
  
  We compared existing and enhanced libraries in predicting variability in three publicly available 450K methylation datasets that collected whole-blood samples. Models were fit separately to each CpG site and used to estimate the additional variability when adjustments for cell composition were made with each library.
  
  
  
  Calculation of the mean difference in the CpG-specific residual sums of squares error between models for an arthritis, aging and metabolic syndrome dataset, indicated that an enhanced library explained significantly more variation across all three datasets (p < 10(-3)).
  
  
  
  Pathologically important immune cell subtypes can explain important variability in epigenome-wide association studies done in blood.
authors.affiliation: Department of Epidemiology, Brown University School of Public Health, Providence, RI 02912, USA.|Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Epidemiology, Brown University School of Public Health, Providence, RI 02912, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Eliot
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, Kansas City, KA 66160, USA.
authors.forename: Devin C
authors.initials: DC
authors.lastname: Koestler
authors.affiliation: Oregon State University College of Public Health & Human Sciences, Corvallis, OR 97331, USA.
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Houseman
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Wetmur
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.affiliation: Department of Epidemiology, Brown University School of Public Health, Providence, RI 02912, USA.|Department of Laboratory Medicine & Pathology, Brown University, Providence, RI 02912, USA.
authors.forename: Karl T
authors.initials: KT
authors.lastname: Kelsey
mesh_terms: D000375:Aging / Q000235:genetics; D001168:Arthritis / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015894:Genome, Human; D055106:Genome-Wide Association Study / Q000592:standards*; D006801:Humans; D007962:Leukocytes / Q000145:classification / Q000378:metabolism*; D024821:Metabolic Syndrome / Q000235:genetics
keywords: 450K methylation library; DNA methylation; aging; arthritis; cell mixture deconvolution; cellular heterogeneity; confounding; differentially methylated regions; epigenome-wide association study; inflammation; lymphocytes