TY - JOUR
T1 - Integrative Genomics Analysis Identifies ACVR1B as a Candidate Causal Gene of Emphysema Distribution
AU - Boueiz, Adel
AU - Pham, Betty
AU - Chase, Robert
AU - Lamb, Andrew
AU - Lee, Sool
AU - Naing, Zun Zar Chi
AU - Cho, Michael
AU - Parker, Margaret M.
AU - Sakornsakolpat, Phuwanat
AU - Hersh, Craig P.
AU - Crapo, James D.
AU - Stergachis, Andrew B.
AU - Tal-Singer, Ruth
AU - DeMeo, Dawn L.
AU - Silverman, Edwin K.
AU - Zhou, Xiaobo
AU - Castaldi, Peter J.
AU - ECLIPSE Investigators
AU - Wouters, Emiel
N1 - Funding Information:
Supported by National Heart, Lung, and Blood Institute (NHLBI) grants K08HL141601-01, U01HL089897, R01HL089897, R01HL089856, R01HL124233, R01HL126596, R01HL113264, P01105339, and P01HL114501. The COPDGene study (COPD Genetic Epidemiology study; NCT00608764) is also supported by the COPD Foundation through contributions made to an industry advisory board comprised of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion. The Norway GenKOLS (Genetics of Chronic Obstructive Lung Disease; GSK code RES11080) and ECLIPSE (Evaluation of Chronic Obstructive Pulmonary Disease to Longitudinally Identify Predictive Surrogate Endpoints; NCT00292552; GSK code SCO104960) studies were funded by GlaxoSmithKline. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHLBI or the National Institutes of Health.
Publisher Copyright:
© 2019 by the American Thoracic Society. All rights reserved.
PY - 2019/4
Y1 - 2019/4
N2 - 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 x 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-beta signaling plays a role in the EABD phenotype.
AB - 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 x 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-beta signaling plays a role in the EABD phenotype.
KW - integrative genomics
KW - emphysema distribution
KW - chronic obstructive pulmonary disease
KW - ACVR1B gene
KW - transforming growth factor-beta signaling
KW - LUNG-VOLUME-REDUCTION
KW - OBSTRUCTIVE PULMONARY-DISEASE
KW - WIDE ASSOCIATION
KW - EXPRESSION
KW - LANDSCAPE
KW - GWAS
U2 - 10.1165/rcmb.2018-0110OC
DO - 10.1165/rcmb.2018-0110OC
M3 - Article
C2 - 30335480
SN - 1044-1549
VL - 60
SP - 388
EP - 398
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
IS - 4
ER -