RT Journal Article
SR Electronic
T1 Identification of FGF7 as a novel susceptibility locus for chronic obstructive pulmonary disease
JF Thorax
JO Thorax
FD BMJ Publishing Group Ltd and British Thoracic Society
SP 1085
OP 1090
DO 10.1136/thoraxjnl-2011-200017
VO 66
IS 12
A1 John M Brehm
A1 Koichi Hagiwara
A1 Yohannes Tesfaigzi
A1 Shannon Bruse
A1 Thomas J Mariani
A1 Soumyaroop Bhattacharya
A1 Nadia Boutaoui
A1 John P Ziniti
A1 Manuel E Soto-Quiros
A1 Lydiana Avila
A1 Michael H Cho
A1 Blanca Himes
A1 Augusto A Litonjua
A1 Francine Jacobson
A1 Per Bakke
A1 Amund Gulsvik
A1 Wayne H Anderson
A1 David A Lomas
A1 Erick Forno
A1 Soma Datta
A1 Edwin K Silverman
A1 Juan C Celedón
YR 2011
UL http://thorax.bmj.com/content/66/12/1085.abstract
AB Rationale 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.Objectives 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.Conclusion 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.