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 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*, ECLIPSE Investigators, Emiel Wouters

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Web of Science)

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 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.

Original languageEnglish
Pages (from-to)388-398
Number of pages11
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume60
Issue number4
DOIs
Publication statusPublished - Apr 2019

Keywords

  • integrative genomics
  • emphysema distribution
  • chronic obstructive pulmonary disease
  • ACVR1B gene
  • transforming growth factor-beta signaling
  • LUNG-VOLUME-REDUCTION
  • OBSTRUCTIVE PULMONARY-DISEASE
  • WIDE ASSOCIATION
  • EXPRESSION
  • LANDSCAPE
  • GWAS

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