Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion.Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations.Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.Measurements and Main Results: We identified and replicated three new genome-wide significant (P < 5 × 10^-8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1, and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility.Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

Keywords: DEPTOR; KIF15; MAD1L1; epidemiology; genetics.

Figure 1.

Manhattan plot of discovery analysis results. The x axis shows chromosomal position, and the y axis shows the −log(P value) for each variant in the discovery genome-wide analysis. The red line shows genome-wide significance (P < 5 × 10⁻⁸), and variants in green met the criteria for further study in the replication analysis (i.e., reached genome-wide significance in the discovery meta-analysis and had P < 0.05 and consistent direction of effects in each study). Genes in gray are previously reported signals that reach significance in the discovery genome-wide meta-analysis. Genes in black are the novel signals identified in the discovery analysis that reach genome-wide significance when meta-analyzing discovery and replication samples. The signals that did not replicate are shown in red. For ease of visualization the y axis has been truncated at 25.

Figure 2.

Region plots of three novel idiopathic pulmonary fibrosis susceptibility loci from discovery genome-wide meta-analysis. Each point represents a variant with chromosomal position on the x axis and the −log(P value) on the y axis. Variants are colored in by linkage disequilibrium with the sentinel variant. Blue lines show the recombination rate, and gene locations are shown at the bottom of the plot. Region plots are shown for the three replicated novel idiopathic pulmonary fibrosis susceptibility loci, i.e., (A) the susceptibility signal on chromosome 3 near KIF15, (B) the susceptibility signal on chromosome 7 near MAD1L1, and (C) the susceptibility signal on chromosome 8 near DEPTOR.