title: Genetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions.
abstract: Deciphering the impact of genetic variants on gene regulation is fundamental to understanding human disease. Although gene regulation often involves long-range interactions, it is unknown to what extent non-coding genetic variants influence distal molecular phenotypes. Here, we integrate chromatin profiling for three histone marks in lymphoblastoid cell lines (LCLs) from 75 sequenced individuals with LCL-specific Hi-C and ChIA-PET-based chromatin contact maps to uncover one of the largest collections of local and distal histone quantitative trait loci (hQTLs). Distal QTLs are enriched within topologically associated domains and exhibit largely concordant variation of chromatin state coordinated by proximal and distal non-coding genetic variants. Histone QTLs are enriched for common variants associated with autoimmune diseases and enable identification of putative target genes of disease-associated variants from genome-wide association studies. These analyses provide insights into how genetic variation can affect human disease phenotypes by coordinated changes in chromatin at interacting regulatory elements.
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Fabian
authors: F
authors: Grubert
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; The European Molecular Biology Laboratory Heidelberg, 69117 Heidelberg, Germany.
authors: Judith B
authors: JB
authors: Zaugg
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Maya
authors: M
authors: Kasowski
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Oana
authors: O
authors: Ursu
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Damek V
authors: DV
authors: Spacek
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Alicia R
authors: AR
authors: Martin
authors: Biomedical Informatics Graduate Training Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Peyton
authors: P
authors: Greenside
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Rohith
authors: R
authors: Srivas
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Doug H
authors: DH
authors: Phanstiel
authors: The European Molecular Biology Laboratory Heidelberg, 69117 Heidelberg, Germany.
authors: Aleksandra
authors: A
authors: Pekowska
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Nastaran
authors: N
authors: Heidari
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Ghia
authors: G
authors: Euskirchen
authors: The European Molecular Biology Laboratory Heidelberg, 69117 Heidelberg, Germany.
authors: Wolfgang
authors: W
authors: Huber
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
authors: Jonathan K
authors: JK
authors: Pritchard
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Carlos D
authors: CD
authors: Bustamante
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; The European Molecular Biology Laboratory Heidelberg, 69117 Heidelberg, Germany.
authors: Lars M
authors: LM
authors: Steinmetz
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
authors: Anshul
authors: A
authors: Kundaje
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: mpsnyder@stanford.edu.
authors: Michael
authors: M
authors: Snyder
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D002877:Chromosomes, Human / Q000737:chemistry / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006657:Histones / Q000378:metabolism; D016045:Human Genome Project; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D040641:Quantitative Trait Loci; D050436:Regulatory Elements, Transcriptional
chemical_list: D002843:Chromatin; D006657:Histones