title: Multistudy fine mapping of chromosome 2q identifies XRCC5 as a chronic obstructive pulmonary disease susceptibility gene.
abstract: BACKGROUND
  Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q.
  
  
  OBJECTIVE
  We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q.
  
  
  METHODS
  Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study.
  
  
  RESULTS
  Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 x 10(-5) across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5.
  
  
  CONCLUSIONS
  By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene.
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA. craig.hersh@channing.harvard.edu
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.forename: Sreekumar G
authors.initials: SG
authors.lastname: Pillai
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhu
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Per
authors.initials: P
authors.lastname: Bakke
authors.forename: Amund
authors.initials: A
authors.lastname: Gulsvik
authors.forename: Dawn L
authors.initials: DL
authors.lastname: DeMeo
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Klanderman
authors.forename: Ross
authors.initials: R
authors.lastname: Lazarus
authors.forename: Augusto A
authors.initials: AA
authors.lastname: Litonjua
authors.forename: David
authors.initials: D
authors.lastname: Sparrow
authors.forename: John J
authors.initials: JJ
authors.lastname: Reilly
authors.forename: Alvar
authors.initials: A
authors.lastname: Agusti
authors.forename: Peter M A
authors.initials: PM
authors.lastname: Calverley
authors.forename: Claudio F
authors.initials: CF
authors.lastname: Donner
authors.forename: Robert D
authors.initials: RD
authors.lastname: Levy
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Make
authors.forename: Peter D
authors.initials: PD
authors.lastname: Paré
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.forename: Jørgen
authors.initials: J
authors.lastname: Vestbo
authors.forename: Emiel F M
authors.initials: EF
authors.lastname: Wouters
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Scholand
authors.forename: Hilary
authors.initials: H
authors.lastname: Coon
authors.forename: John
authors.initials: J
authors.lastname: Hoidal
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
mesh_terms: D017668:Age of Onset; D000368:Aged; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D004265:DNA Helicases / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D000072200:Ku Autoantigen; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D058255:Protease Nexins; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics; D012907:Smoking / Q000009:adverse effects
chemical_list: D016564:Amyloid beta-Protein Precursor; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen
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