title: High density methylation QTL analysis in human blood via next-generation sequencing of the methylated genomic DNA fraction.
abstract: BACKGROUND
  Genetic influence on DNA methylation is potentially an important mechanism affecting individual differences in humans. We use next-generation sequencing to assay blood DNA methylation at approximately 4.5 million loci, each comprising 2.9 CpGs on average, in 697 normal subjects. Methylation measures at each locus are tested for association with approximately 4.5 million single nucleotide polymorphisms (SNPs) to exhaustively screen for methylation quantitative trait loci (meQTLs).
  
  
  RESULTS
  Using stringent false discovery rate control, 15 % of methylation sites show genetic influence. Most meQTLs are local, where the associated SNP and methylation site are in close genomic proximity. Distant meQTLs and those spanning different chromosomes are less common. Most local meQTLs encompass common SNPs that alter CpG sites (CpG-SNPs). Local meQTLs encompassing CpG-SNPs are enriched in regions of inactive chromatin in blood cells. In contrast, local meQTLs lacking CpG-SNPs are enriched in regions of active chromatin and transcription factor binding sites. Of 393 local meQTLs that overlap disease-associated regions from genome-wide studies, a high percentage encompass common CpG-SNPs. These meQTLs overlap active enhancers, differentiating them from CpG-SNP meQTLs in inactive chromatin.
  
  
  CONCLUSIONS
  Genetic influence on the human blood methylome is common, involves several heterogeneous processes and is predominantly dependent on local sequence context at the meQTL site. Most meQTLs involve CpG-SNPs, while sequence-dependent effects on chromatin binding are also important in regions of active chromatin. An abundance of local meQTLs resulting from methylation of CpG-SNPs in inactive chromatin suggests that many meQTLs lack functional consequence. Integrating meQTL and Roadmap Epigenomics data could assist fine-mapping efforts.
authors.affiliation: Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, 410 North 12th Street, Richmond, VA, 23298, USA. jlmcclay@vcu.edu.|Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, 1112 East Clay Street, Richmond, VA, 23298, USA. jlmcclay@vcu.edu.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: McClay
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, 1112 East Clay Street, Richmond, VA, 23298, USA. ashabalin@vcu.edu.
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Shabalin
authors.affiliation: Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Mikhail G
authors.initials: MG
authors.lastname: Dozmorov
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, 1112 East Clay Street, Richmond, VA, 23298, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Adkins
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, 1112 East Clay Street, Richmond, VA, 23298, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Kumar
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, 1112 East Clay Street, Richmond, VA, 23298, USA.
authors.forename: Srilaxmi
authors.initials: S
authors.lastname: Nerella
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, 1112 East Clay Street, Richmond, VA, 23298, USA.
authors.forename: Shaunna L
authors.initials: SL
authors.lastname: Clark
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.|Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Bergen
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Hultman
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Patrik K E
authors.initials: PK
authors.lastname: Magnusson
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.|Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Sullivan
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, 1112 East Clay Street, Richmond, VA, 23298, USA.
authors.forename: Karolina A
authors.initials: KA
authors.lastname: Aberg
authors.affiliation: Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, 1112 East Clay Street, Richmond, VA, 23298, USA.
authors.forename: Edwin J C G
authors.initials: EJ
authors.lastname: van den Oord
mesh_terms: D001769:Blood / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA