title: Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain.
abstract: A fundamental challenge in the post-genome era is to understand and annotate the consequences of genetic variation, particularly within the context of human tissues. We present a set of integrated experiments that investigate the effects of common genetic variability on DNA methylation and mRNA expression in four human brain regions each from 150 individuals (600 samples total). We find an abundance of genetic cis regulation of mRNA expression and show for the first time abundant quantitative trait loci for DNA CpG methylation across the genome. We show peak enrichment for cis expression QTLs to be approximately 68,000 bp away from individual transcription start sites; however, the peak enrichment for cis CpG methylation QTLs is located much closer, only 45 bp from the CpG site in question. We observe that the largest magnitude quantitative trait loci occur across distinct brain tissues. Our analyses reveal that CpG methylation quantitative trait loci are more likely to occur for CpG sites outside of islands. Lastly, we show that while we can observe individual QTLs that appear to affect both the level of a transcript and a physically close CpG methylation site, these are quite rare. We believe these data, which we have made publicly available, will provide a critical step toward understanding the biological effects of genetic variation.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: J Raphael
authors.initials: JR
authors.lastname: Gibbs
authors.forename: Marcel P
authors.initials: MP
authors.lastname: van der Brug
authors.forename: Dena G
authors.initials: DG
authors.lastname: Hernandez
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.forename: Shiao-Lin
authors.initials: SL
authors.lastname: Lai
authors.forename: Sampath
authors.initials: S
authors.lastname: Arepalli
authors.forename: Allissa
authors.initials: A
authors.lastname: Dillman
authors.forename: Ian P
authors.initials: IP
authors.lastname: Rafferty
authors.forename: Juan
authors.initials: J
authors.lastname: Troncoso
authors.forename: Robert
authors.initials: R
authors.lastname: Johnson
authors.forename: H Ronald
authors.initials: HR
authors.lastname: Zielke
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.forename: Dan L
authors.initials: DL
authors.lastname: Longo
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
mesh_terms: D001921:Brain / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D012333:RNA, Messenger