title: Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci.
abstract: Genetic risk loci have been identified for a wide range of diseases through genome-wide association studies (GWAS), but the relevant functional mechanisms have been identified for only a small proportion of these GWAS-identified loci. By integrating results from the largest current GWAS of chronic obstructive disease (COPD) with expression quantitative trait locus (eQTL) analysis in whole blood and sputum from 121 subjects with COPD from the ECLIPSE Study, this analysis identifies loci that are simultaneously associated with COPD and the expression of nearby genes (COPD eQTLs). After integrative analysis, 19 COPD eQTLs were identified, including all four previously identified genome-wide significant loci near HHIP, FAM13A, and the 15q25 and 19q13 loci. For each COPD eQTL, fine mapping and colocalization analysis to identify causal shared eQTL and GWAS variants identified a subset of sites with moderate-to-strong evidence of harboring at least one shared variant responsible for both the eQTL and GWAS signals. Transcription factor binding site (TFBS) analysis confirms that multiple COPD eQTL lead SNPs disrupt TFBS, and enhancer enrichment analysis for loci with the strongest colocalization signals showed enrichment for blood-related cell types (CD3 and CD4+ T cells, lymphoblastoid cell lines). In summary, integrative eQTL and GWAS analysis confirms that genetic control of gene expression plays a key role in the genetic architecture of COPD and identifies specific blood-related cell types as likely participants in the functional pathway from GWAS-associated variant to disease phenotype.
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, USA, Division of General Internal Medicine and Primary Care and peter.castaldi@channing.harvard.edu.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Castaldi
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, USA, Pulmonary and Critical Care Division, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, USA, Pulmonary and Critical Care Division, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, USA.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mcgeachie
authors.affiliation: Division of General Internal Medicine and Primary Care and Pulmonary and Critical Care Division, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
authors.forename: Bartolome
authors.initials: B
authors.lastname: Celli
authors.affiliation: Haukeland University Hospital, Bergen, Norway.
authors.forename: Per
authors.initials: P
authors.lastname: Bakke
authors.affiliation: Haukeland University Hospital, Bergen, Norway.
authors.forename: Amund
authors.initials: A
authors.lastname: Gulsvik
authors.affiliation: University College London, London, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.affiliation: Department of Medicine, National Jewish Health, Denver.
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.affiliation: Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Rennard
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Harshfield
authors.affiliation: Harvard School of Public Health, Boston, MA, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
authors.affiliation: GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Tal-Singer
authors.affiliation: GlaxoSmithKline, Uxbridge, UK and.
authors.forename: John H
authors.initials: JH
authors.lastname: Riley
authors.affiliation: Harvard School of Public Health, Boston, MA, USA, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, USA, Pulmonary and Critical Care Division, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, USA.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Carey
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, USA, Pulmonary and Critical Care Division, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, USA, Pulmonary and Critical Care Division, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
mesh_terms: D016022:Case-Control Studies; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15; D019295:Computational Biology; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D040641:Quantitative Trait Loci; D012907:Smoking