title: Identification of FGF7 as a novel susceptibility locus for chronic obstructive pulmonary disease.
abstract: BACKGROUND
  Traditional genome-wide association studies (GWASs) of large cohorts of subjects with chronic obstructive pulmonary disease (COPD) have successfully identified novel candidate genes, but several other plausible loci do not meet strict criteria for genome-wide significance after correction for multiple testing.
  
  
  OBJECTIVE
  The authors hypothesise that by applying unbiased weights derived from unique populations we can identify additional COPD susceptibility loci. Methods The authors performed a homozygosity haplotype analysis on a group of subjects with and without COPD to identify regions of conserved homozygosity haplotype (RCHHs). Weights were constructed based on the frequency of these RCHHs in case versus controls, and used to adjust the p values from a large collaborative GWAS of COPD.
  
  
  RESULTS
  The authors identified 2318 RCHHs, of which 576 were significantly (p<0.05) over-represented in cases. After applying the weights constructed from these regions to a collaborative GWAS of COPD, the authors identified two single nucleotide polymorphisms (SNPs) in a novel gene (fibroblast growth factor-7 (FGF7)) that gained genome-wide significance by the false discovery rate method. In a follow-up analysis, both SNPs (rs12591300 and rs4480740) were significantly associated with COPD in an independent population (combined p values of 7.9E-7 and 2.8E-6, respectively). In another independent population, increased lung tissue FGF7 expression was associated with worse measures of lung function.
  
  
  CONCLUSIONS
  Weights constructed from a homozygosity haplotype analysis of an isolated population successfully identify novel genetic associations from a GWAS on a separate population. This method can be used to identify promising candidate genes that fail to meet strict correction for multiple testing.
authors.affiliation: Division of Pediatric Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Brehm
authors.forename: Koichi
authors.initials: K
authors.lastname: Hagiwara
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Tesfaigzi
authors.forename: Shannon
authors.initials: S
authors.lastname: Bruse
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Mariani
authors.forename: Soumyaroop
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Nadia
authors.initials: N
authors.lastname: Boutaoui
authors.forename: John P
authors.initials: JP
authors.lastname: Ziniti
authors.forename: Manuel E
authors.initials: ME
authors.lastname: Soto-Quiros
authors.forename: Lydiana
authors.initials: L
authors.lastname: Avila
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.forename: Blanca
authors.initials: B
authors.lastname: Himes
authors.forename: Augusto A
authors.initials: AA
authors.lastname: Litonjua
authors.forename: Francine
authors.initials: F
authors.lastname: Jacobson
authors.forename: Per
authors.initials: P
authors.lastname: Bakke
authors.forename: Amund
authors.initials: A
authors.lastname: Gulsvik
authors.forename: Wayne H
authors.initials: WH
authors.lastname: Anderson
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Erick
authors.initials: E
authors.lastname: Forno
authors.forename: Soma
authors.initials: S
authors.lastname: Datta
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.forename: Juan C
authors.initials: JC
authors.lastname: Celedón
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003364:Costa Rica / Q000453:epidemiology; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000235:genetics*; D015870:Gene Expression; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D012129:Respiratory Function Tests; D012307:Risk Factors; D012907:Smoking / Q000453:epidemiology
chemical_list: C496453:FGF7 protein, human; D051523:Fibroblast Growth Factor 7