Integrative Genomics Analysis Identifies ACVR1B as a Candidate Causal Gene of Emphysema Distribution

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 3 10 25 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 1 , CD8 1 , 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-b signaling plays a role in the EABD phenotype. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

Identification of an emphysema-associated genetic variant near TGFB2 with regulatory effects in lung fibroblasts

“…With respect to the lung, TGF-β family proteins participate in normal lung development and are dysregulated in COPD, emphysema, asthma, and pulmonary fibrosis (Verhamme et al, 2015; Morris et al, 2003; Thomas et al, 2016). Genetic variants near TGF-β superfamily members TGFB2 (Castaldi et al, 2014; Cho et al, 2014), ACVR1B (Boueiz et al, 2019), LTBP4 (Wain et al, 2017), and BMP6 (Loth et al, 2014) have been identified in GWAS for lung function and COPD, but prior to this study the region near ACVR1B was the only one linked to a gene in the TGF-β pathway through functional studies (Boueiz et al, 2019). Our findings demonstrate that the emphysema-associated variant rs1690789 is located in an active gene regulatory region in human lung fibroblasts that interacts with the promoter region of TGFB2 and regulates TGFB2 expression.…”

Pharmacogenomics of chronic obstructive pulmonary disease

“…Most common have been GWAS of lung function, the largest of which included over 400,000 subjects and identified 279 genetic loci [55]. GWAS have been performed for hyperinflation [56] and emphysema distribution [57,58], two phenotypes that are relevant for lung volume reduction therapies. Although exacerbations are an important outcome in clinical trials, no GWAS for COPD exacerbations have been published.…”

“…Emphysema can be assessed based on quantitative analysis of chest CT scans [67]. GWAS have identified genome-wide significant associations with quantitative measures of emphysema [68,69], emphysema patterns [70], and emphysema distribution [57,58]. Some of the emphysema associations overlap with COPD GWAS findings, including genes such as HHIP and FAM13A, which have been demonstrated to influence emphysema in mouse smoking models [71,72].…”

Characterization of a COPD-Associated NPNT Functional Splicing Genetic Variant in Human Lung Tissue via Long-Read Sequencing

“…As a result, expression quantitative trait locus (eQTL) studies that associate genetic variants to gene expression values have been used to identify functional gene targets of GWAS-identified loci. In COPD, this approach has identified putative causal variants affecting the expression of HHIP 2 , FAM13A 3 , TGFB2 4 , and ACVR1B 5 . However, eQTL studies do not capture all of the potentially relevant functional mechanisms through which causal variants may alter gene expression.…”