Background: Upper lobe predominant emphysema is an important predictor of the response to lung volume reduction procedures. Several genetic risk loci associated with emphysema distribution have been identified through genome-wide association studies (GWAS). To further characterize these associations, we performed functional evaluations of the identified SNPs using available resources of expression quantitative trait loci (eQTL) and cell-type-specific epigenomic annotations. Results: SNPs with P-values <5x10-5 in the largest current GWAS meta-analysis of emphysema distribution in smokers (Boueiz A. et al, AJRCCM 2017) were analyzed. 99 distinct emphysema distribution-associated loci had significant associations with multi-tissue eQTL from the Genotype-Tissue Expression (GTEx) project and whole blood eQTL from the COPDGene study at FDR 10%. 14 of these loci showed strong evidence of one shared causal variant for emphysema distribution and an eQTL in multiple tissues (colocalization posterior probability ≥ 0.9). 17 Roadmap cell types exhibited enrichment in DNase-I hypersensitive peaks, DNaseI hotspots, enhancer marks, or digital DNaseI footprinting (P-value < 0.05), with the strongest enrichment observed in CD4+, CD8+, and regulatory T cells. A region near the ACVR1B gene demonstrated significant colocalization in lung eQTL and DNase-I hypersensitive region that is active in multiple cell types. Reporter assays confirmed allele-specific regulatory activity for the emphysema distribution-associated variant, rs7962469, near ACVR1B. Conclusions: This integrative analysis highlights candidate causal genes, regulatory variations, and specific cell types that may contribute to the pathogenesis of emphysema distribution. These findings will enable more accurate functional validation studies, better understanding of emphysema distribution biology, and ultimately, personalized patient care.

Integrative genomics analysis identifies ACVR1B as a candidate causal gene of emphysema distribution in non-alpha 1-antitrypsin deficient smokers