Integrative Genomics Analysis Identifies ACVR1B as a Candidate Causal Gene of Emphysema Distribution
Year: 2018
Type: article
Abstract: Genome-wide association studies (GWAS) have identified multiple associations with emphysema apicobasal distribution (EABD), but the biological functions of these variants are unknown. To characterize the functions of EABD-associated variants, we integrated GWAS results with 1) expression quantitative trait loci (eQTL) from the Genotype Tissue Expression (GTEx) project and subjects in the COPDGene (Genetic Epidemiology of COPD) study and 2) cell type epigenomic marks from the Roadmap Epigenomics project. On the basis of these analyses, we selected a variant near ACVR1B (activin A receptor type 1B) for functional validation. SNPs from 168 loci with P values less than 5 × 10−5 in the largest GWAS meta-analysis of EABD were analyzed. Eighty-four loci overlapped eQTL, with 12 of these loci showing greater than 80% likelihood of harboring a single, shared GWAS and eQTL causal variant. Seventeen cell types were enriched for overlap between EABD loci and Roadmap Epigenomics marks (permutation P < 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. 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 ACVR1B expression, indicating that transforming growth factor-β signaling plays a role in the EABD phenotype. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Identifying Genetic Determinants of Severe, Early-Onset COPD, INTEGRATIVE GENOMICS OF CLINICAL SUBTYPES IN COPDGENE, Systems Biology of Airway Disease, (2 of 2) Genetic Epidemiology of COPD, (1 of 2) Genetic Epidemiology of COPD, (2 of 2) Genetic Epidemiology of COPD, Using Integrative Genomics To Identify and Characterize Emphysema-Associated eQTL, Community Assist of Southern Arizona, (1 of 2) Genetic Epidemiology of COPD, SYSTEMS GENOMICS OF THE ASTHMA-COPD OVERLAP SYNDROME, Metabolic Control of Stemness in lung epithelial progenitors by FAM13A, Clinical significance and genetic determinants of novel imaging measures of emphysema distribution in 9,743 smokers, Genetics of Smoke-Altered LTA4H in COPD, Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers, SYSTEMS APPROACHES TO THE EPIDEMIOLOGY, GENETICS AND GENOMICS OF LUNG DISEASES
OpenAlex ID: W2897210781