title: Genome-wide association identifies regulatory Loci associated with distinct local histogram emphysema patterns.
abstract: BACKGROUND
  Emphysema is a heritable trait that occurs in smokers with and without chronic obstructive pulmonary disease. Emphysema occurs in distinct pathologic patterns, but the genetic determinants of these patterns are unknown.
  
  
  OBJECTIVE
  To identify genetic loci associated with distinct patterns of emphysema in smokers and investigate the regulatory function of these loci.
  
  
  METHODS
  Quantitative measures of distinct emphysema patterns were generated from computed tomography scans from smokers in the COPDGene Study using the local histogram emphysema quantification method. Genome-wide association studies (GWAS) were performed in 9,614 subjects for five emphysema patterns, and the results were referenced against enhancer and DNase I hypersensitive regions from ENCODE and Roadmap Epigenomics cell lines.
  
  
  RESULTS
  Genome-wide significant associations were identified for seven loci. Two are novel associations (top single-nucleotide polymorphism rs379123 in MYO1D and rs9590614 in VMA8) located within genes that function in cell-cell signaling and cell migration, and five are in loci previously associated with chronic obstructive pulmonary disease susceptibility (HHIP, IREB2/CHRNA3, CYP2A6/ADCK, TGFB2, and MMP12). Five of these seven loci lay within enhancer or DNase I hypersensitivity regions in lung fibroblasts or small airway epithelial cells, respectively. Enhancer enrichment analysis for top GWAS associations (single-nucleotide polymorphisms associated at P < 5 × 10(-6)) identified multiple cell lines with significant enhancer enrichment among top GWAS loci, including lung fibroblasts.
  
  
  CONCLUSIONS
  This study demonstrates for the first time genetic associations with distinct patterns of pulmonary emphysema quantified by computed tomography scan. Enhancer regions are significantly enriched among these GWAS results, with pulmonary fibroblasts among the cell types showing the strongest enrichment.
authors.affiliation: 1 Channing Division of Network Medicine and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Castaldi
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.forename: Raúl
authors.initials: R
authors.lastname: San José Estépar
authors.forename: Merry-Lynn N
authors.initials: ML
authors.lastname: McDonald
authors.forename: Nan
authors.initials: N
authors.lastname: Laird
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.forename: George
authors.initials: G
authors.lastname: Washko
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping / Q000379:methods / Q000706:statistics & numerical data; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods* / Q000706:statistics & numerical data; D006801:Humans; D008137:Longitudinal Studies; D008168:Lung / Q000000981:diagnostic imaging; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011656:Pulmonary Emphysema / Q000000981:diagnostic imaging* / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects*; D036542:Tomography, Spiral Computed / Q000379:methods
keywords: COPD; emphysema; gene regulation; genetics; spiral computed tomography