Integrative Genomics Analysis Identifies ACVR1B as a Candidate Causal Gene of Emphysema Distribution
Adel Boueiz, Betty Pham, Robert Chase, Andrew Lamb, Sool Lee, Zun Zar Chi Naing, Michael H Cho, Margaret M Parker, Phuwanat Sakornsakolpat, Craig P Hersh, James D Crapo, Andrew B Stergachis, Ruth Tal-Singer, Dawn L DeMeo, Edwin K Silverman, Xiaobo Zhou, Peter J Castaldi, COPDGene investigators, by Core Units:, ECLIPSE Investigators:, GenKOLS Investigators:, James D Crapo, Edwin K Silverman, Barry J Make, Elizabeth A Regan, Terri Beaty, Ferdouse Begum, Peter J Castaldi, Michael Cho, Dawn L DeMeo, Adel Boueiz, Marilyn G Foreman, Eitan Halper-Stromberg, Lystra P Hayden, Craig P Hersh, Jacqueline Hetmanski, Brian D Hobbs, John E Hokanson, Nan Laird, Christoph Lange, Sharon M Lutz, Merry-Lynn McDonald, Margaret M Parker, Dandi Qiao, Elizabeth A Regan, Edwin K Silverman, Emily S Wan, Sungho Won, Phuwanat Sakornsakolpat, Dmitry Prokopenko, Mustafa Al Qaisi, Harvey O Coxson, Teresa Gray, MeiLan K Han, Eric A Hoffman, Stephen Humphries, Francine L Jacobson, Philip F Judy, Ella A Kazerooni, Alex Kluiber, David A Lynch, John D Newell Jr, Elizabeth A Regan, James C Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Douglas Stinson, Berend C Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, George Washko, Carla G Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Camille Moore, Matt Strand, Carla G Wilson, John E Hokanson, John Hughes, Gregory Kinney, Sharon M Lutz, Katherine Pratte, Kendra A Young, Surya Bhatt, Jessica Bon, MeiLan K Han, Barry Make, Carlos Martinez, Susan Murray, Elizabeth Regan, Xavier Soler, Carla G Wilson, Russell P Bowler, Katerina Kechris, Farnoush Banaei-Kashani, Y Ivanov, K Kostov, J Bourbeau, M Fitzgerald, P Hernandez, K Killian, R Levy, F Maltais, D O'Donnell, J Krepelka, J Vestbo, E Wouters, D Quinn, P Bakke, M Kosnik, A Agusti, J Sauleda, Y Feschenko, V Gavrisyuk, L Yashina, N Monogarova, P Calverley, D Lomas, W MacNee, D Singh, J Wedzicha, A Anzueto, S Braman, R Casaburi, B Celli, G Giessel, M Gotfried, G Greenwald, Rancho Mirage, N Hanania, D Mahler, B Make, S Rennard, C Rochester, P Scanlon, D Schuller, F Sciurba, A Sharafkhaneh, T Siler, E Silverman, A Wanner, R Wise, R ZuWallack, H Coxson, C Crim, L Edwards, D Lomas, W MacNee, E Silverman, R Tal-Singer, J Vestbo, J Yates, A Agusti, P Calverley, B Celli, C Crim, B Miller, W MacNee, S Rennard, R Tal-Singer, E Wouters, J Yates, Per Bakke, Amund Gulsvik, Adel Boueiz, Betty Pham, Robert Chase, Andrew Lamb, Sool Lee, Zun Zar Chi Naing, Michael H Cho, Margaret M Parker, Phuwanat Sakornsakolpat, Craig P Hersh, James D Crapo, Andrew B Stergachis, Ruth Tal-Singer, Dawn L DeMeo, Edwin K Silverman, Xiaobo Zhou, Peter J Castaldi, COPDGene investigators, by Core Units:, ECLIPSE Investigators:, GenKOLS Investigators:, James D Crapo, Edwin K Silverman, Barry J Make, Elizabeth A Regan, Terri Beaty, Ferdouse Begum, Peter J Castaldi, Michael Cho, Dawn L DeMeo, Adel Boueiz, Marilyn G Foreman, Eitan Halper-Stromberg, Lystra P Hayden, Craig P Hersh, Jacqueline Hetmanski, Brian D Hobbs, John E Hokanson, Nan Laird, Christoph Lange, Sharon M Lutz, Merry-Lynn McDonald, Margaret M Parker, Dandi Qiao, Elizabeth A Regan, Edwin K Silverman, Emily S Wan, Sungho Won, Phuwanat Sakornsakolpat, Dmitry Prokopenko, Mustafa Al Qaisi, Harvey O Coxson, Teresa Gray, MeiLan K Han, Eric A Hoffman, Stephen Humphries, Francine L Jacobson, Philip F Judy, Ella A Kazerooni, Alex Kluiber, David A Lynch, John D Newell Jr, Elizabeth A Regan, James C Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Douglas Stinson, Berend C Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, George Washko, Carla G Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Camille Moore, Matt Strand, Carla G Wilson, John E Hokanson, John Hughes, Gregory Kinney, Sharon M Lutz, Katherine Pratte, Kendra A Young, Surya Bhatt, Jessica Bon, MeiLan K Han, Barry Make, Carlos Martinez, Susan Murray, Elizabeth Regan, Xavier Soler, Carla G Wilson, Russell P Bowler, Katerina Kechris, Farnoush Banaei-Kashani, Y Ivanov, K Kostov, J Bourbeau, M Fitzgerald, P Hernandez, K Killian, R Levy, F Maltais, D O'Donnell, J Krepelka, J Vestbo, E Wouters, D Quinn, P Bakke, M Kosnik, A Agusti, J Sauleda, Y Feschenko, V Gavrisyuk, L Yashina, N Monogarova, P Calverley, D Lomas, W MacNee, D Singh, J Wedzicha, A Anzueto, S Braman, R Casaburi, B Celli, G Giessel, M Gotfried, G Greenwald, Rancho Mirage, N Hanania, D Mahler, B Make, S Rennard, C Rochester, P Scanlon, D Schuller, F Sciurba, A Sharafkhaneh, T Siler, E Silverman, A Wanner, R Wise, R ZuWallack, H Coxson, C Crim, L Edwards, D Lomas, W MacNee, E Silverman, R Tal-Singer, J Vestbo, J Yates, A Agusti, P Calverley, B Celli, C Crim, B Miller, W MacNee, S Rennard, R Tal-Singer, E Wouters, J Yates, Per Bakke, Amund Gulsvik
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).
Trial registration: ClinicalTrials.gov NCT00608764 NCT00292552.
Keywords: gene; chronic obstructive pulmonary disease; emphysema distribution; integrative genomics; transforming growth factor-β signaling.
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Source: PubMed