3 research outputs found
A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease
Genome-wide association studies (GWASs) have identified regions associated with chronic obstructive pulmonary disease (COPD). GWASs of other diseases have shown an approximately 10-fold overrepresentation of nonsynonymous variants, despite limited exonic coverage on genotyping arrays. We hypothesized that a large-scale analysis of coding variants could discover novel genetic associations with COPD, including rare variants with large effect sizes. We performed a meta-analysis of exome arrays from 218,399 controls and 33,851 moderate-to-severe COPD cases. All exome-wide significant associations were present in regions previously identified by GWAS. We did not identify any novel rare coding variants with large effect sizes. Within GWAS regions on chromosomes 5q, 6p, and 15q, four coding variants were conditionally significant (P < 0.00015) when adjusting for lead GWAS single-nucleotide polymorphisms A common gasdermin B (GSDMB) splice variant (rs11078928) previously associated with a decreased risk for asthma was nominally associated with a decreased risk for COPD [minor allele frequency (MAF)=0.46, P = 1.8e-4]. Two stop variants in coiled-coil a-helical rod protein 1 (CCHCR1), a gene involved in regulating cell proliferation, were associated with COPD (both P < 0.0001). The SERPINA1 Z allele was associated with a random-effects odds ratio of 1.43 for COPD (95% confidence interval = 1.17â1.74), though with marked heterogeneity across studies. Overall, COPD-associated exonic variants were identified in genes involved in DNA methylation, cell-matrix interactions, cell proliferation, and cell death. In conclusion, we performed the largest exome array meta-analysis of COPD to date and identified potential functional coding variants. Future studies are needed to identify rarer variants and further define the role of coding variants in COPD pathogenesis
Overlap of genetic risk between interstitial lung abnormalities and idiopathic pulmonary fibrosis
Rationale
Interstitial lung abnormalities (ILA) are associated with the highest genetic risk locus for IPF;
however, the extent to which there is additional overlap with IPF, or unique associations among
those with ILA is not known.
Objectives
To perform a genome-wide association study (GWAS) of ILA.
Methods: ILA and the subpleural-predominant subtype were assessed on chest computed
tomography (CT) scans in the AGES, COPDGene, Framingham Heart, ECLIPSE, MESA, and
SPIROMICS studies. We performed a GWAS of ILA in each cohort and combined the results
using a meta-analysis. We assessed for overlapping associations in independent GWASs of
IPF.
Measurements and Main Results
Genome-wide genotyping data were available in 1,699 ILA cases and 10,274 controls. The
MUC5B promoter variant rs35705950 was significantly associated with both ILA (p=2.6x10-27)
and subpleural ILA (p=1.6x10-29). We discovered novel genome-wide associations near IPO11
(rs6886640, p=3.8x10-8
) and FCF1P3 (rs73199442, p=4.8x10-8
) with ILA, and HTRE1
(rs7744971, p=4.2x10-8
) with subpleural-predominant ILA. These novel associations were not
associated with IPF. Of 12 previously reported IPF GWAS loci, 5 (DPP9, DSP, FAM13A, IVD,
and MUC5B) were significantly associated (p<0.05/12) with ILA.
Conclusions
In a GWAS of ILA in six studies, we confirmed the association with a MUC5B promoter variant
and found strong evidence for an effect of previously described IPF loci; however, novel ILA
associations were not associated with IPF. These findings highlight common and suggest
distinct genetically-driven biologic pathways between ILA and IPF
Genetic Associations and Architecture of Asthma-COPD Overlap
Background
Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone.
Research Question
What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?
Study Design and Methods
We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P
Results
We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P
Interpretation
We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.</p