Integrative genomics analysis identifies <i>ACVR1B</i> as a candidate causal gene of emphysema distribution in non-alpha 1-antitrypsin deficient smokers

Boueiz, Adel; Chase, Robert; Lamb, Andrew; S, Lee; Zzc, Naing; Cho, MH; Mm, Parker; Hersh, C.P.; Jd, Crapo; Ab, Stergachis; Tal‐Singer, Ruth; Dl, DeMeo; Silverman, EK; Castaldi, PJ

doi:10.1101/189100

Cited by 2 publications

(3 citation statements)

References 51 publications

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“…We also performed functional evaluation and demonstrated allelespecific enhancer activity for an emphysema distribution-associated variant that alters the lung expression of ACVR1B (activin A receptor type 1B), an activin receptor in the transforming growth factor (TGF)-b signaling pathway. Some of these results were previously reported in the form of an abstract (13).…”

supporting

confidence: 55%

“…We analyzed 11,532 non-alpha-1 antitrypsin-deficient current and former smokers with complete genotype and computed tomographic densitometry data from four cohorts: the COPDGene NHW (Genetic Epidemiology of COPD study non-Hispanic whites), COPDGene African Americans, the GenKOLS (Genetics of Chronic Obstructive Lung Disease), and the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) studies. Detailed descriptions, including study populations, genotyping quality control, and genotyping imputation, were published previously (12)(13)(14).…”

Section: Study Populationsmentioning

confidence: 99%

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

Boueiz¹,

Pham²,

Chase³

et al. 2019

Am J Respir Cell Mol Biol

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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).

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supporting

confidence: 55%

Section: Study Populationsmentioning

confidence: 99%

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

Boueiz¹,

Pham²,

Chase³

et al. 2019

Am J Respir Cell Mol Biol

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“…For example, multiple studies have suggested the TGFB pathway is associated with COPD (50), and the TGFB2 locus was associated with COPD in GWAS (51). Our study identified ACVR2B as a potential candidate; of interest, ACVR1B, an activin receptor which interacts with ACVR2B (52) was identified in a network-informed genetic association study of COPD (53) and in an integrative analysis of emphysema distribution (54).…”

Section: Discussionmentioning

confidence: 71%

Whole exome sequencing analysis in severe chronic obstructive pulmonary disease

Qiao

Ameli

Prokopenko

et al. 2018

Human Molecular Genetics

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Chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide, is substantially influenced by genetic factors. Alpha-1 antitrypsin deficiency demonstrates that rare coding variants of large effect can influence COPD susceptibility. To identify additional rare coding variants in patients with severe COPD, we conducted whole exome sequencing analysis in 2543 subjects from two family-based studies (Boston Early-Onset COPD Study and International COPD Genetics Network) and one case-control study (COPDGene). Applying a gene-based segregation test in the family-based data, we identified significant segregation of rare loss of function variants in TBC1D10A and RFPL1 (P-value < 2x10-6), but were unable to find similar variants in the case-control study. In single-variant, gene-based and pathway association analyses, we were unable to find significant findings that replicated or were significant in meta-analysis. However, we found that the top results in the two datasets were in proximity to each other in the protein-protein interaction network (P-value = 0.014), suggesting enrichment of these results for similar biological processes. A network of these association results and their neighbors was significantly enriched in the transforming growth factor beta-receptor binding and cilia-related pathways. Finally, in a more detailed examination of candidate genes, we identified individuals with putative high-risk variants, including patients harboring homozygous mutations in genes associated with cutis laxa and Niemann-Pick Disease Type C. Our results likely reflect heterogeneity of genetic risk for COPD along with limitations of statistical power and functional annotation, and highlight the potential of network analysis to gain insight into genetic association studies.

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Integrative genomics analysis identifies ACVR1B as a candidate causal gene of emphysema distribution in non-alpha 1-antitrypsin deficient smokers

Abstract: Background: Several genetic risk loci associated with emphysema apico-basal distribution

Cited by 2 publications

References 51 publications

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

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

Whole exome sequencing analysis in severe chronic obstructive pulmonary disease

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