title: Systematic localization of common disease-associated variation in regulatory DNA.
abstract: Genome-wide association studies have identified many noncoding variants associated with common diseases and traits. We show that these variants are concentrated in regulatory DNA marked by deoxyribonuclease I (DNase I) hypersensitive sites (DHSs). Eighty-eight percent of such DHSs are active during fetal development and are enriched in variants associated with gestational exposure-related phenotypes. We identified distant gene targets for hundreds of variant-containing DHSs that may explain phenotype associations. Disease-associated variants systematically perturb transcription factor recognition sequences, frequently alter allelic chromatin states, and form regulatory networks. We also demonstrated tissue-selective enrichment of more weakly disease-associated variants within DHSs and the de novo identification of pathogenic cell types for Crohn's disease, multiple sclerosis, and an electrocardiogram trait, without prior knowledge of physiological mechanisms. Our results suggest pervasive involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Maurano
authors.forename: Richard
authors.initials: R
authors.lastname: Humbert
authors.forename: Eric
authors.initials: E
authors.lastname: Rynes
authors.forename: Robert E
authors.initials: RE
authors.lastname: Thurman
authors.forename: Eric
authors.initials: E
authors.lastname: Haugen
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Alex P
authors.initials: AP
authors.lastname: Reynolds
authors.forename: Richard
authors.initials: R
authors.lastname: Sandstrom
authors.forename: Hongzhu
authors.initials: H
authors.lastname: Qu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Brody
authors.forename: Anthony
authors.initials: A
authors.lastname: Shafer
authors.forename: Fidencio
authors.initials: F
authors.lastname: Neri
authors.forename: Kristen
authors.initials: K
authors.lastname: Lee
authors.forename: Tanya
authors.initials: T
authors.lastname: Kutyavin
authors.forename: Sandra
authors.initials: S
authors.lastname: Stehling-Sun
authors.forename: Audra K
authors.initials: AK
authors.lastname: Johnson
authors.forename: Theresa K
authors.initials: TK
authors.lastname: Canfield
authors.forename: Erika
authors.initials: E
authors.lastname: Giste
authors.forename: Morgan
authors.initials: M
authors.lastname: Diegel
authors.forename: Daniel
authors.initials: D
authors.lastname: Bates
authors.forename: R Scott
authors.initials: RS
authors.lastname: Hansen
authors.forename: Shane
authors.initials: S
authors.lastname: Neph
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sabo
authors.forename: Shelly
authors.initials: S
authors.lastname: Heimfeld
authors.forename: Antony
authors.initials: A
authors.lastname: Raubitschek
authors.forename: Steven
authors.initials: S
authors.lastname: Ziegler
authors.forename: Chris
authors.initials: C
authors.lastname: Cotsapas
authors.forename: Nona
authors.initials: N
authors.lastname: Sotoodehnia
authors.forename: Ian
authors.initials: I
authors.lastname: Glass
authors.forename: Shamil R
authors.initials: SR
authors.lastname: Sunyaev
authors.forename: Rajinder
authors.initials: R
authors.lastname: Kaul
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
mesh_terms: D000483:Alleles; D002843:Chromatin / Q000378:metabolism / Q000648:ultrastructure; D003424:Crohn Disease / Q000235:genetics; D004247:DNA / Q000235:genetics*; D003850:Deoxyribonuclease I / Q000378:metabolism; D004194:Disease / Q000235:genetics*; D004562:Electrocardiography; D047109:Fetal Development; D005333:Fetus / Q000378:metabolism; D053263:Gene Regulatory Networks; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D009103:Multiple Sclerosis / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D050436:Regulatory Elements, Transcriptional; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D014157:Transcription Factors; D004247:DNA; D003850:Deoxyribonuclease I