Integrative genomics analysis identifies ACVR1B as a candidate causal gene of emphysema distribution in non-alpha 1-antitrypsin deficient smokers
Year: 2017
Type: preprint
Abstract: ABSTRACT Background Several genetic risk loci associated with emphysema apico-basal distribution (EABD) have been identified through genome-wide association studies (GWAS), but the biological functions of these variants are unknown. To characterize gene regulatory functions of EABD-associated variants, we integrated EABD GWAS results with 1) a multi-tissue panel of expression quantitative trait loci (eQTL) from subjects with COPD and the GTEx project and 2) epigenomic marks from 127 cell types in the Roadmap Epigenomics project. Functional validation was performed for a variant near ACVR1B . Results SNPs from 168 loci with P-values<5x10 -5 in the largest GWAS meta-analysis of EABD (Boueiz A. et al, AJRCCM 2017) were analyzed. 54 loci overlapped eQTL regions from our multi-tissue panel, and 7 of these loci showed a high probability of harboring a single, shared GWAS and eQTL causal variant (colocalization posterior probability≥0.9). 17 cell types exhibited greater than expected overlap between EABD loci and DNase-I hypersensitive peaks, DNaseI hotspots, enhancer marks, or digital DNaseI footprints (permutation P-value < 0.05), with the strongest enrichment observed in CD4 + , CD8 + , and regulatory T cells. A region near ACVR1B demonstrated significant colocalization with a lung eQTL and overlapped DNase-I hypersensitive regions in multiple cell types, and reporter assays in human bronchial epithelial cells confirmed allele-specific regulatory activity for the lead variant, rs7962469. Conclusions Integrative analysis highlights candidate causal genes, regulatory variants, and cell types that may contribute to the pathogenesis of emphysema distribution. These findings will enable more accurate functional validation studies and better understanding of emphysema distribution biology.
DOI: 10.1101/189100
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Pfizer, AstraZeneca, GlaxoSmithKline, Brigham and Women's Hospital, University of Minnesota, Johns Hopkins University, University of Pittsburgh, COPD Foundation, Sunovion, Temple University, National Jewish Health, Morehouse School of Medicine, University of California, San Diego, Anschutz Medical Campus, University of Colorado, National Heart, Lung, and Blood Institute
Awards: Identifying Genetic Determinants of Severe, Early-Onset COPD, G226397431, (2 of 2) Genetic Epidemiology of COPD, G4405771736, G4606287987, G46194766, (1 of 2) Genetic Epidemiology of COPD, Using Integrative Genomics To Identify and Characterize Emphysema-Associated eQTL, G7403697370, G754838926, G7949433598, G8450059190, Genetics of Smoke-Altered LTA4H in COPD, G8643874822, G8819318481, Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
OpenAlex ID: W2767099191