Integrative Genomics Analysis Identifies ACVR1B as a Candidate Causal Gene of Emphysema Distribution.

RATIONALE: Genome-wide association studies (GWAS) have identified multiple associations with emphysema apico-basal distribution (EABD), but the biological functions of these variants are unknown.

METHODS: To characterize the functions of EABD-associated variants, we integrated GWAS results with 1) expression quantitative trait loci (eQTL) from the GTEx project and subjects in the COPDGene Study and 2) cell type epigenomic marks from the Roadmap Epigenomics project. Based on these analyses, we selected a variant near ACVR1B for functional validation.

RESULTS: SNPs from 168 loci with P-values<5x10-5 in the largest GWAS meta-analysis of EABD were analyzed. Eighty-four loci overlapped eQTL, with 12 of these loci showing > 80% likelihood of harboring a single, shared GWAS and eQTL causal variant. Seventeen cell types were enriched for overlap between EABD loci and Roadmap epigenomic marks (Permutation P-value<0.05), with the strongest enrichment observed in CD4+, CD8+, and regulatory T cells. We selected a putative causal variant, rs7962469, associated with ACVR1B expression in lung tissue for additional functional investigation, and reporter assays confirmed allele-specific regulatory activity for this variant in human bronchial epithelial and Jurkat immune cell lines. ACVR1B expression levels exhibit a nominally significant association with emphysema distribution.

CONCLUSIONS: EABD-associated loci are preferentially enriched in regulatory elements of multiple cell types, most notably T-cell subsets. Multiple EABD loci colocalize to regulatory elements that are active across multiple tissues and cell types, and functional analyses confirm the presence of an EABD-associated functional variant that regulates ACRV1B expression, indicating that TGF-β signaling plays a role in the EABD phenotype.