Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis

Abstract

We performed a genome-wide association study of non-Hispanic, white individuals with fibrotic idiopathic interstitial pneumonias (IIPs; n = 1,616) and controls (n = 4,683), with follow-up replication analyses in 876 cases and 1,890 controls. We confirmed association with TERT at 5p15, MUC5B at 11p15 and the 3q26 region near TERC, and we identified seven newly associated loci (Pmeta = 2.4 × 10(-8) to 1.1 × 10(-19)), including FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13) and chromosomal regions 7q22 and 15q14-15. Our results suggest that genes involved in host defense, cell-cell adhesion and DNA repair contribute to risk of fibrotic IIPs.

Figure 1

GWAS results at 439,828 SNPs with 1616 cases and 4683 controls under additive model. SNPs above red line were genome-wide significant at P < 5×10^−8. These SNPs and SNPs between red and blue lines, corresponding to 5×10⁻⁸ < P-value <.0001, were selected for follow-up in 876 cases and 1890 controls.

Figure 2

Locus-specific plots corresponding to discovery GWAS results for all loci reaching genome-wide significance in the GWAS discovery analysis and meta-analysis of the discovery and replication results (a–g). For each plot, the –log₁₀ P values (y axis) of the SNPs are shown according to their chromosomal positions (x axis). The significant loci are on chromosomes 5p15 (a), 6p24 (b), 7q22 (c), 11p15 (d), 15q14-15 (e), 17q21 (f), and 19p13 (g). The estimated recombination rates (cM/Mb) from the HapMap Project (NCBI Build 36) are shown as light blue lines, and the genomic locations of genes within the regions of interest in the NCBI Build 36 human assembly are shown as arrows. SNPs shown in red, orange, green, light blue and blue have r² ≥ 0.8, r² ≥ 0.6, r² ≥ 0.4, r² ≥ 0.2 and r² < 0.2 with the most highly-associated SNP, respectively. SNP annotation key: Circles, squares, triangles, star (*), and squares with an x represent no annotation, synonymous or 3′ UTR, nonsynonymous, TFBScons and MCS44 placental, respectively. Genotyped SNPs shown; analogous plots with imputed SNP genotypes are shown in Supplementary Figure 2.

Figure 3

Locus-specific plots corresponding to discovery GWAS results for four additional loci reaching genome-wide significance after the meta-analysis of the discovery and replication results (a–d). For each plot, the –log₁₀ P values (y axis) of the SNPs are shown according to their chromosomal positions (x axis). The significant loci are on chromosomes 3q26 (a), 4q22 (b), 10q24 (c), and 13q34 (d). The estimated recombination rates (cM/Mb) from the HapMap Project (NCBI Build 36) are shown as light blue lines, and the genomic locations of genes within the regions of interest in the NCBI Build 36 human assembly are shown as arrows. SNPs shown in red, orange, green, light blue and blue have r² ≥ 0.8, r² ≥ 0.6, r² ≥ 0.4, r² ≥ 0.2 and r² < 0.2 with the most highly-associated SNP, respectively. SNP annotation key: Circles, squares, triangles, star (*), and squares with an x represent no annotation, synonymous or 3′ UTR, nonsynonymous, TFBScons and MCS44 placental, respectively. Genotyped SNPs shown; analogous plots with imputed SNP genotypes are shown in Supplementary Figure 3.

Figure 4

Relative expression of DSP in lung tissue from 100 cases and 94 controls. a) relative expression by case/control status b) relative expression by genotype at rs2076295 in DSP.

Figure 4

Relative expression of DSP in lung tissue from 100 cases and 94 controls. a) relative expression by case/control status b) relative expression by genotype at rs2076295 in DSP.