Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis

Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known. To perform a genome-wide association study (GWAS) of ILAs. ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF. Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs ( = 2.6 × 10) and subpleural ILAs ( = 1.6 × 10). We discovered novel genome-wide associations near (rs6886640,  = 3.8 × 10) and (rs73199442,  = 4.8 × 10) with ILAs, and near (rs7744971,  = 4.2 × 10) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (, , , , and ) were significantly associated ( < 0.05/12) with ILAs. In a GWAS of ILAs in six studies, we confirmed the association with a promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.