The association of genome-wide significant spirometric loci with chronic obstructive pulmonary disease susceptibility

Abstract

Two recent metaanalyses of genome-wide association studies conducted by the CHARGE and SpiroMeta consortia identified novel loci yielding evidence of association at or near genome-wide significance (GWS) with FEV(1) and FEV(1)/FVC. We hypothesized that a subset of these markers would also be associated with chronic obstructive pulmonary disease (COPD) susceptibility. Thirty-two single-nucleotide polymorphisms (SNPs) in or near 17 genes in 11 previously identified GWS spirometric genomic regions were tested for association with COPD status in four COPD case-control study samples (NETT/NAS, the Norway case-control study, ECLIPSE, and the first 1,000 subjects in COPDGene; total sample size, 3,456 cases and 1,906 controls). In addition to testing the 32 spirometric GWS SNPs, we tested a dense panel of imputed HapMap2 SNP markers from the 17 genes located near the 32 GWS SNPs and in a set of 21 well studied COPD candidate genes. Of the previously identified GWS spirometric genomic regions, three loci harbored SNPs associated with COPD susceptibility at a 5% false discovery rate: the 4q24 locus including FLJ20184/INTS12/GSTCD/NPNT, the 6p21 locus including AGER and PPT2, and the 5q33 locus including ADAM19. In conclusion, markers previously associated at or near GWS with spirometric measures were tested for association with COPD status in data from four COPD case-control studies, and three loci showed evidence of association with COPD susceptibility at a 5% false discovery rate.

Trial registration: ClinicalTrials.gov NCT00292552.

Figures

Figure 1.

Schematic overview of association tests for chronic obstructive pulmonary disease (COPD) susceptibility. Single-nucleotide polymorphisms (SNPs) were identified from the CHARGE and SpiroMeta spirometric genome-wide association (GWA) metaanalyses and a set of previously studied COPD candidate genes. Two association tests were conducted: (1) a SNP level “replication” for 32 SNPs extracted from the CHARGE and SpiroMeta publications and (2) a gene-based extended association analysis for the 17 genes located near the 32 SNPs above in addition to 21 other COPD candidate genes. The 32 SNPs are a subset of the 6,534 genotyped and imputed fine mapping SNPs. Of these 32 SNPs, 25 are from CHARGE, 6 are from SpiroMeta, and 1 was reported in both studies. GWA-MA = genome-wide association metaanalysis; GWS = genome-wide significance.

Figure 2.

Localization plots showing the results of association testing for COPD susceptibility loci at 4q24 (A), 6p21 (B), and 5q33 (C). The red diamond marks the most strongly associated SNP in our study, and the blue triangles represent SNPs identified in pulmonary function GWA metaanalyses. Analyzed genes are depicted with green arrows, and recombination rates based on HapMap data are represented as blue triangles.

Figure 3.

Localization plot demonstrating the strongest association from the gene-based extended association analysis, rs11134242 in the spirometric GWA-identified gene ADCY2. The red diamond marks the most strongly associated SNP in our study, and the blue triangles represent SNPs identified in spirometric GWA metaanalyses. These results suggest that the signal observed in our study may arise from a locus distinct from that observed in the study by Hancock and colleagues.