title: Methylation QTLs are associated with coordinated changes in transcription factor binding, histone modifications, and gene expression levels.
abstract: DNA methylation is an important epigenetic regulator of gene expression. Recent studies have revealed widespread associations between genetic variation and methylation levels. However, the mechanistic links between genetic variation and methylation remain unclear. To begin addressing this gap, we collected methylation data at ∼300,000 loci in lymphoblastoid cell lines (LCLs) from 64 HapMap Yoruba individuals, and genome-wide bisulfite sequence data in ten of these individuals. We identified (at an FDR of 10%) 13,915 cis methylation QTLs (meQTLs)-i.e., CpG sites in which changes in DNA methylation are associated with genetic variation at proximal loci. We found that meQTLs are frequently associated with changes in methylation at multiple CpGs across regions of up to 3 kb. Interestingly, meQTLs are also frequently associated with variation in other properties of gene regulation, including histone modifications, DNase I accessibility, chromatin accessibility, and expression levels of nearby genes. These observations suggest that genetic variants may lead to coordinated molecular changes in all of these regulatory phenotypes. One plausible driver of coordinated changes in different regulatory mechanisms is variation in transcription factor (TF) binding. Indeed, we found that SNPs that change predicted TF binding affinities are significantly enriched for associations with DNA methylation at nearby CpGs.
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Banovich
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America; Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Xun
authors.initials: X
authors.lastname: Lan
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America; Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Graham
authors.initials: G
authors.lastname: McVicker
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America; Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Bryce
authors.initials: B
authors.lastname: van de Geijn
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America; Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Jacob F
authors.initials: JF
authors.lastname: Degner
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America; Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: John D
authors.initials: JD
authors.lastname: Blischak
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Julien
authors.initials: J
authors.lastname: Roux
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America; Department of Genetics, Stanford University, Stanford, California, United States of America; Department of Biology, Stanford University, Stanford, California, United States of America; Howard Hughes Medical Institute, Stanford University, Stanford, California, United States of America.
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Pritchard
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Gilad
mesh_terms: D001665:Binding Sites; D002461:Cell Line, Transformed; D019295:Computational Biology; D019175:DNA Methylation; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D005838:Genotype; D006657:Histones / Q000378:metabolism*; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D040641:Quantitative Trait Loci; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D006657:Histones; D014157:Transcription Factors