Identification of Functional Variants in the FAM13A Chronic Obstructive Pulmonary Disease Genome-Wide Association Study Locus by Massively Parallel Reporter Assays

Rationale: The identification of causal variants responsible for disease associations from genome-wide association studies (GWASs) facilitates functional understanding of the biological mechanisms by which those genetic variants influence disease susceptibility.Objective: We aim to identify causal variants in or near the FAM13A (family with sequence similarity member 13A) GWAS locus associated with chronic obstructive pulmonary disease (COPD).Methods: We used an integrated approach featuring conditional genetic analysis, massively parallel reporter assays (MPRAs), traditional reporter assays, chromatin conformation capture assays, and clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing to characterize COPD-associated regulatory variants in the FAM13A region in human bronchial epithelial cell lines.Measurements and Main Results: Conditional genetic association suggests the presence of two independent COPD association signals in FAM13A. MPRAs identified 45 regulatory varian...