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Thoraxjnl-2011-200017 1.6

Thorax Online First, published on September 15, 2011 as 10.1136/thoraxjnl-2011-200017
Identification of FGF7 as a novel susceptibility locusfor chronic obstructive pulmonary disease John M Brehm,1 Koichi Hagiwara,2 Yohannes Tesfaigzi,3 Shannon Bruse,3Thomas J Mariani,4 Soumyaroop Bhattacharya,4 Nadia Boutaoui,1 John P Ziniti,5Manuel E Soto-Quiros,6 Lydiana Avila,6 Michael H Cho,5,7,8 Blanca Himes,5Augusto A Litonjua,5,7,8,9 Francine Jacobson,10 Per Bakke,11 Amund Gulsvik,11Wayne H Anderson,12 David A Lomas,13 Erick Forno,14 Soma Datta,5Edwin K Silverman,5,7,8,15 Juan C Celedo 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 < Can information from isolated populations plausible loci do not meet strict criteria for genome-wide improve our ability to detect novel genetic significance after correction for multiple testing.
variants in genome-wide association studies 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 < We identified statistically significant polymor- Children’s Hospital of Pittsburghof UPMC, 4401 Penn Avenue, haplotype analysis on a group of subjects with and phisms in a novel chronic obstructive pulmonary without COPD to identify regions of conserved disease (COPD) gene (FGF7), which we repli- 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 (homozygosity haplotype analysis) for identi- 576 were significantly (p<0.05) over-represented in fying genomic regions that are inherited froma common ancestor, and use this information to cases. After applying the weights constructed fromthese regions to a collaborative GWAS of COPD, the authors identified two single nucleotide polymorphisms genetic variants that are associated withincreased risk of disease.
(SNPs) in a novel gene (fibroblast growth factor-7(FGF7)) that gained genome-wide significance by thefalse discovery rate method. In a follow-up analysis, bothSNPs (rs12591300 and rs4480740) were significantly significant results after correction for multiple associated with COPD in an independent population testing. Weighting the results of GWASs according to prior information (eg, from linkage studies) may respectively). In another independent population, significantly improve the power to detect associations increased lung tissue FGF7 expression was associated that do not meet genome-wide (GW) significance.4 with worse measures of lung function.
Homozygosity mapping is a promising technique Conclusion Weights constructed from a homozygosity to identifying regions of the genome that are more haplotype analysis of an isolated population successfully identify novel genetic associations from a GWAS on Although initially developed to identify rare a separate population. This method can be used to susceptibility mutations for monogenic traits in identify promising candidate genes that fail to meet strict families,5 homozygosity mapping has recently been successfully applied to the study of complexdiseases.6 7 While techniques vary, the conceptunderlying all homozygosity haplotype (HH)methods is that regions of homozygosity are more likely to contain disease-susceptibility loci in affected subjects than in unaffected individuals.8 (GWASs) have identified novel susceptibility loci for complex diseases such as chronic obstructive morphism (SNP) arrays, Miyazawa et al developed pulmonary disease (COPD).1e3 Because the effect a novel variation of homozygosity mapping that tests whether multiple subjects share the same variants is modest, GWASs of complex diseases require large sample sizes to achieve statistically constructed a region of conserved homozygosity Brehm JM, Hagiwara K, Tesfaigzi Y, et al. Thorax (2011). doi:10.1136/thoraxjnl-2011-200017 Copyright Article author (or their employer) 2011. Produced by BMJ Publishing Group Ltd (& BTS) under licence.
haplotype (RCHH) that reflects the transmission of the haplotype multicentre ECLIPSE study.12 All controls were current or former from a founder population. In theoretical simulations, this smokers with normal spirometry, and all cases with COPD had method was shown to be a viable method to detect disease- moderate to very severe disease according to the Global Initiative susceptibility loci in recently admixed populations.9 We hypoth- for Chronic Obstructive Lung Disease classification.13 esised that application of this method to a genetic isolate in CostaRica would result in detection of an over-representation of regions of conserved homozygosity in subjects affected with COPD The top SNPs in novel genes were replicated in a cohort of 1845 compared with unaffected subjects. In this report, we first identify smoking adults in New Mexico, 424 (23%) of whom were regions of conserved homozygosity in Costa Ricans and then classified with COPD based on an FEV1/FVC ratio below the show that weights derived from these regions can be applied to fifth percentile of the predicted value, also referred to as the GWASs in non-isolated populations to identify novel disease- lower limit of normal.14 Of the 1845 participants, 1411 (77%) susceptibility loci for COPD. Using this approach, we identify were Caucasian and 313 (17%) were Hispanic. The protocols for a novel COPD candidate gene (fibroblast growth factor-7 (FGF7)).
subject recruitment and data collection for the Lovelace SmokersCohort have been previously described in detail.15 The two SNPs (rs12591300 and rs4480740) were genotyped by allelic discrimi- nation using Taqman assay (Applied Biosystems, Foster City, The primary study population consisted of 58 subjects with California, USA). The caseecontrol association analysis was first COPD (cases) and 57 subjects without COPD (controls) in the performed in all subjects, and then separately in Caucasians and Genetic Epidemiology of COPD in Costa Rica study. Cases were Hispanics. All analyses were adjusted for age, gender and pack- recruited from patients attending four adult hospitals in San José years of cigarette smoking; the analysis of all subjects was (Costa Rica) and their affiliated clinics, and through newspaper additionally adjusted for self-declared ethnicity.
advertisements. Control subjects were recruited from individualsattending a smoking-cessation clinic at the Institute for Phar- maco-dependency in San José, and through newspaper adver- For the top novel candidate genes, we examined the correlation of tisements. To ensure their descent from the founder population gene expression in lung tissue with COPD intermediate pheno- of the Central Valley of Costa Rica (which is predominantly of types (FEV1 and FEV1/FVC ratio) in a previously published Spanish and Native American ancestry), all participants were COPD biomarker discovery study.16 This cohort consists of 56 required to have at least six great-grandparents born in the subjects with varying degrees of obstruction who underwent Central Valley. Additional inclusion criteria for cases were ages lung resection for a solitary pulmonary nodule. RNA expression profiling was completed using the Affymetrix U133 Plus 2.0 array, e71 years, physician-diagnosed COPD, $10 pack-years of cigarette smoking, a forced expiratory volume in one second as previously described.16 Expression correlation with quantita- tive phenotypes was conducted as previously described.16 1) #65% predicted and an FEV1/forced vital capacity (FVC) ratio of #70% after bronchodilator administration (180 mg ofalbuterol by metered dose inhaler). Controls were recruited on the basis of the same criteria for age and smoking history, but they had to have no physician-diagnosed COPD and normal RCHHs were identified using the method described by Miyazawa spirometry. Exclusion criteria for cases and controls included et al.9 In brief, for any given individual all heterozygous SNPs history of chronic pre-existing chronic lung disease (eg, bron- were ignored and the SNP location was scored with the value of chiectasis) and severe a-1-antitrypsin deficiency (for cases), the allele for that subject. Subjects are compared only across SNPs based on molecular phenotyping. The baseline characteristics of that are scored. RCHHs are defined by runs of SNPs that share the this cohort are in listed in the online supplementary table 2.
same allele at the homozygous locations across multiple subjects, Written consent was obtained from participating subjects.
ignoring heterozygous SNPs. The size of the shared segments The study was approved by the institutional review boards of between any two individuals was set at 3.0 cM (roughly and the Hospital Nacional de Niños (San José, Costa Rica), Partners approximately three million base pairs), which in theoretical Healthcare System (Boston, Massachusetts, USA), and partici- work conducted by Miyazawa et al9 reduced the false positive pating National Emphysema Treatment Trial (NETT), Evalua- and false negative rates of discovery. A theoretical ancestral tion of COPD Longitudinally to Identify Predictive Surrogate segment was then constructed from the largest subgroup of Endpoints (ECLIPSE) and Norway centres.
subjects sharing a particular RCHH (see online supplementaryfigure 1). While any two subjects must have at least 3.0 cM of sharing, the size may be much smaller when comparing across High-density SNP genotyping was performed using the Illumina multiple subjects (online supplementary figure 2). If more than Quad 610 platform at the Channing Laboratory, Boston, one ancestral region is identified at a particular chromosomal Massachusetts, USA. Cases and controls were randomly location, the region shared by the most number of subjects is used distributed among batches, and each batch contained a replicate (online supplementary figure 3). The total number of cases and sample. All subjects had an SNP call rate >95%. After quality controls sharing this ancestral allele is used to calculate a p value control measures (see online supplementary table 1), a total of based on a standard normal distribution.
558 929 SNPs were acceptable for analysis.
For the primary analysis of the collaborative COPD cohort, logistic regression analysis was performed under an additive Collaborative COPD cohorts for the primary GWAS genetic model for each SNP, adjusting for age, pack-years of Three populations with a total of 2940 cases and 1380 controls smoking and the first 16 principal components (to adjust for were used for the primary GWAS: (1) subjects in a caseecontrol population stratification). The p values from all RCHHs iden- study of COPD in Norway (838 cases and 791 controls)3; (2) tified in Costa Rica were then used to construct a cumulative subjects in the NETT (366 cases) and the Normative Aging Study weight for each SNP from the recent GWAS of COPD in the (414 controls)10 11 and (3) 1736 cases and 175 controls from the combined cohort of Norway, ECLIPSE and NETTeNormative Brehm JM, Hagiwara K, Tesfaigzi Y, et al. Thorax (2011). doi:10.1136/thoraxjnl-2011-200017 Aging Study using the method developed by Roeder et al.4 there was an RCHH containing FAM13A identified in the Costa Briefly, the weighting method utilises prior information (in this Rican cohort, it was only seen in one case and no controls.
case, the p value representing the degree of over-representationof a region of the genome in cases versus controls) to upweight or downweight p values from an association study (in this case, The top two SNPs in or near FGF7 were genotyped in the 1845 the GWAS of COPD in the collaborative cohort). In order to smoking adults in the Lovelace Smokers Cohort. The minor maintain an overall a level of 0.05, the assigned weights across alleles of both SNPs conferred increased odds for COPD in the the genome average to 1. For this study, SNPs that did not fall whole population in the same direction as the original collabo- inside of an RCHH (and therefore did not have a p value) were rative COPD cohort (table 2). Among the Hispanic subgroup, assigned a p value of 1 (and therefore a weight approaching the effect size was larger and in the same direction for both zero). This is a more conservative approach than excluding these SNPs, but only rs12591300 showed a significant association with SNPs from consideration. The method then calculates a false- discovery rate (FDR) using the method described by Benjaminiand Hochberg17 to correct for multiple testing.
The RCHHs were created and compared with HHAnalysis Our previous studies indicate that gene expression patterns (available at http://www.hhanalysis.com). Association analysis associated with quantitative, intermediate COPD phenotypes was performed using PLINK V.1.07 (http://pngu.mgh.harvard.
are most informative for the discovery of disease-associated edu/purcell/plink). The weighting procedure was performed genes.16 18 19 We examined disease-associated expression using software developed by Roeder et al4 (http://wpicr.wpic.
patterns for our novel candidate genes in a previously published pitt.edu/wpiccompgen/). All other statistical analysis was GW expression data set from 56 subjects with varying degrees performed using R V.2.9.0 (http://www.R-project.org).
of airflow obstruction (assessed by spirometric measures of lungfunction (FEV1 and FEV1/FVC ratio)).16 Expression of FGF7 (asdefined by multiple and independent probe sets) was signifi- cantly negatively correlated with both FEV Identification of RCHHs in Costa Rica and construction of 1/FVC ratio (nominal p value <0.01), indicating increased expression associated with increased disease severity.
In total, 2318 RCHHs were identified in the Costa Rican cohort.
Expression in COPD subjects was increased compared with Of these 2318 regions, 576 were significantly (p<0.05) over- control subjects, but the difference was not statistically represented in cases compared with controls; none of the regions significant. PSMA4 expression was not correlated with lung were significantly more frequent in controls than cases. The function and was not differentially expressed in cases versus median size of the significant regions was 105 kb, and the largest was 7.2 Mb. Online supplementary table 3 shows the top 20 pvalues representing 100 RCHHs in Costa Rica.
Each SNP in the combined collaborative COPD cohort was then mapped to an RCHH and assigned the p value of the whole While successful in identifying novel candidate genes, GWASs of region. SNPs that did not map to an RCHH were assigned a p complex traits are unlikely to identify all potential common value of 1. The mapped p values across all genotyped SNPs were disease-susceptibility variants because of limited power if strict then used to create weights using a cumulative distribution criteria for GW significance are applied. In the absence of a very function. The algorithm is constructed so that the mean weight large sample size, novel methods are needed to identify disease- across all SNPs is 1: some SNPs are upweighted and a much susceptibility variants not meeting GW significance. We identi- larger fraction is downweighted. The nominal p value is divided fied RCHHs for COPD in a GW caseecontrol study in Costa by the weight to obtain the weighted p value.
Rica. After applying a weighting method based on the degree ofsignificance of these regions to a GWAS of COPD cases and controls of European descent, we identified two SNPs in a novel We applied the weights derived from the HH analysis above to candidate gene for COPD (FGF7) and demonstrated that several reanalyse GW genotypic data in a cohort of subjects of European SNPs in the previously identified candidate genes IREB2 and descent that was previously employed for a traditional GWAS of CHRNA3 met GW criteria for statistical significance. An SNP in COPD. After weighting, 14 SNPs were significant at an FDR- another novel gene (PSMA4) was GW significant after corrected a of 0.05. The top five SNPs from the unweighted weighting. However, expression of PSMA4 in the lung was not GWAS retained their original ranks, but several SNPs that did associated with COPD phenotypes, and thus the observed not achieve GW significance in the traditional GW association association is likely due to linkage disequilibrium with the analysis became more statistically significant and moved higher nearby genes CHRNA3 and IREB2. We then replicated the two in the list (table 1). Of these SNPs, those in the gene for FAM13A FGF7 SNPs in an independent cohort of smoking adults, and were identified in the original analysis of the GWAS,1 and SNPs showed that they are both significantly associated in the same in IREB218 and CHRNA33 have been implicated in COPD direction with COPD. Notably, the effect sizes in Hispanics are affection status in prior candidate-gene and GWASs. Two of the larger than in the overall cohort, suggesting that these alleles other SNPs lie in two novel candidate genes for COPD, FGF7 confer greater risk in this population. This Hispanic population and proteasome subunit, a-type, 4 (PSMA4) (figure 1). The in New Mexico has a similar proportion of European and Native RCHH in Costa Rica that contains FGF7 was present in seven American ancestry as the Costa Rican cohort,20 21 so another cases and no controls, and the RCHH containing PSMA4 was likely possibility is that patterns of linkage disequilibrium may present in five cases and no controls.
be different between Hispanics and Caucasians in this genomic The regions containing the genes CHRNA3 and IREB2 were region, and that these SNPs are tagging a haplotype or func- also over-represented in cases compared with controls (p<0.05), tional SNP in the Hispanic subjects. Additionally, there was and after weighting they were GW significant by FDR. While a trend towards increased lung tissue expression of FGF7 in an Brehm JM, Hagiwara K, Tesfaigzi Y, et al. Thorax (2011). doi:10.1136/thoraxjnl-2011-200017 FDR significant* results from weighted GWAS *An FDR-corrected p value of 1.43Ee6 was used as the cut-off for genome-wide significance.
yResults previously published by Cho et al.1 zThe weighted p value is the original p value divided by the weight constructed from the RCHH (not shown).
xp Values for individual cohorts are the original, unweighted p values.
COPD, chronic obstructive pulmonary disease; ECLIPSE, Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; FDR, false-discovery rate; FGF7, fibroblast growth factor-7;GWAS, genome-wide association study; NAS, Normative Aging Study; NETT, National Emphysema Treatment Trial; PSMA4, proteasome subunit, a-type, 4; RCHH, region of conservedhomozygosity haplotype; SNP, single nucleotide polymorphism.
independent cohort of COPD subjects, in whom there was There are several plausible methods for weighting chromo- a significant negative correlation between FGF7 expression and somal regions in GWAS, including upweighting previously identified candidate genes, coding variants, exons and promoter chromosome 15, before (top) and afterweighting. rs4480740 (Green) is in thegene FGF7 and rs2036534 (blue) is inthe promoter of PSMA4. The red lineindicates the FDR corrected a level forgenome-wide significance. FDR, false-discovery rate; FGF7, fibroblast growthfactor-7; PSMA4, proteasome subunit, Brehm JM, Hagiwara K, Tesfaigzi Y, et al. Thorax (2011). doi:10.1136/thoraxjnl-2011-200017 Combined p values for replication of FGF7 SNPs *Fisher’s combined p value using original two-sided p values.
COPD, chronic obstructive pulmonary disease; FGF7, fibroblast growth factor-7; SNP, single nucleotide polymorphism.
regions. However, these weighting strategies work counter to power of the algorithm to detect them. Genetic and historical one of the strengths of a GWAS: its hypothesis-free nature.
data for the population of the Central Valley of Costa Rica Using HHs as a weighting method avoids the pitfall of these suggest that the first three assumptions are met. As in most other weighting strategies because they are constructed using association studies of complex disease, the effect size of a risk a hypothesis-free method, so the weights are unbiased with allele is likely small to moderate at most, and we expect that this One of the main strengths of our study is that it shows the Whereas other homozygosity mapping methods are primarily power of using HH analysis in an isolated population to inves- designed to detect recessive alleles, the HHAnalysis method tigate common diseases. While our sample size was small, instead uses homozygosity to identify ancestral regions inherited Miyazawa et al9 have previously shown in simulated data that from a common ancestor. These regions from a common ancestor HH analysis has the ability to identify the region containing an can harbour risk alleles that operate under recessive, dominant or SNP inherited identity-by-descent from a distant common additive models. However, the HHAnalysis algorithm would also ancestor using only 45 cases and 45 controls. In our own detect copy number variation that results in the deletion of data, we were able to show that the previously identified a single allele. While this may explain a fraction of the regions candidate genes IREB2 and CHRNA3 fall within an RCHH that identified, the top novel SNPs identified in FGF7 do not fall is significantly over-represented in subjects with COPD. When within known regions of copy number variation according to the combined with results from a weighted GWAS in an indepen- dent cohort with adequate sample size, we were able to show In summary, we have shown that weights obtained from HH that variants in these genes are significant after correction for analysis in an isolated population can improve the power to detect novel variants in GWAS in non-isolates. In addition to Two novel genes are contained within significant regions of confirming results for previously identified variants in IREB2 conserved homozygosity, and after weighting they are signifi- and CHRNA3, we have identified variants in a novel candidate cant by FDR correction. The first, FGF7, was identified in gene (FGF7) for COPD. The validity of this gene is supported cultured human embryonic lung fibrobasts,22 and plays a role in by replication in an independent cohort of smoking adults, and promoting wound healing23 and protecting airway epithelium expression data showing consistent and significant patterns from oxidant injury in mice.24 One of the SNPs identified in this associated with COPD intermediate lung function phenotypes.
study (rs4480740) is in an intron of FGF7, and the other Further analysis of these genes in the Costa Rican cohort (rs12591300) lies immediately upstream of FGF7 in an intron of and functional studies should yield insights into the causative hypothetical protein LOC196951. In a GWAS of FEV1 in the SNPs or haplotypes that underlie the associations identified in British 1958 Birth Cohort, five out of the nine SNPs genotyped in FGF7 were significantly (p<0.05) associated with differencesin lung function, although not the two SNPs identified in this study.25 FGF7 has been shown to protect against oxidative stress Division of Pediatric Pulmonary Medicine, Allergy, and Immunology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA response specifically in the lung epithelium,24 so increases in 2Saitama Medical University Hospital and Institute, Saitama, Japan expression associated with disease progression may indicate 3Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA a greater burden of injury. A limitation of our study is the lack of 4University of Rochester Medical Center, Rochester, New York, USA5 experimental evidence for an effect(s) of the SNPs identified in Channing Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA Division of Pediatric Pulmonology, Hospital Nacional de Nin on gene expression. We hypothesise that these SNPs cause 7Division of Pulmonary/Critical Care Medicine, Brigham and Women’s Hospital, Boston, decreased expression of FGF7, which could affect antioxidant mechanisms protecting against detrimental effects of cigarette 8Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, smoking on the lung. Alternatively, FGF7 may play a role in disease susceptibility through its role in epithelial development Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA 10Department of Radiology, Brigham and Women’s Hospital, Boston, Massachusetts, during embryogenesis by influencing epithelial responses to cigarette smoke. Since it is unclear whether increased FGF7 11Haukeland University Hospital and Institute of Medicine, University of Bergen, expression is a marker of exposure to oxidant injury or a cause of epithelial damage, further work must be done to characterise the GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina, role of these SNPs on FGF7 expression.
13Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK The HHAnalysis algorithm works best under certain 14Division of Pediatric Pulmonology, Department of Pediatrics, University of Miami, assumptions, namely that (1) the risk alleles were introduced into the population from a population of common ancestors Center for Genomic Medicine, Brigham and Women’s Hospital, Boston, within the last several hundred years, (2) the target population is genetically isolated, (3) the number of common ancestors Funding The Genetic Epidemiology of COPD in Costa Rica is supported by grant introducing the risk allele is small and that (4) the risk of the R01HL073373 from the National Heart, Lung, and Blood Institute. The NationalEmphysema Treatment Trial (NETT) is supported by contracts with the National Heart, disease allele is moderate to high. Violations of these assump- Lung, and Blood Institute (N01HR76101, N01HR76102, N01HR76103, N01HR76104, tions reduce the theoretical expected size of the RCHH and/or N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, the association of the RCHH with disease, which reduces the N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, Brehm JM, Hagiwara K, Tesfaigzi Y, et al. Thorax (2011). doi:10.1136/thoraxjnl-2011-200017 N01HR76115, N01HR76116, N01HR76118, N01HR76119), the Centers for Medicare Bell B, Rose CL, Damon A. The Normative Aging Study: an interdisciplinary and and Medicaid Services (CMS) and the Agency for Healthcare Research and Quality longitudinal study of health and aging. Aging Hum Dev 1972;3:5e17.
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susceptibility locus for chronic obstructive
pulmonary disease

John M Brehm, Koichi Hagiwara, Yohannes Tesfaigzi, et al.
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