Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is characterised by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratios per standard deviation of the risk score (~6 alleles) (95% confidence interval) 1.24 (1.20-1.27), P=5.05x10-49) and we observed a 3.7 fold difference in COPD risk between highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in development, elastic fibres and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

Granulocyte-CSF links destructive inflammation and comorbidities in obstructive lung disease

“…It is surprising, given the important progress in identifying novel gene variants in genome-wide association studies (8,9), that the trait most strongly associated with COPD in large prospective biomarker studies is a simple elevation in peripheral WBC count (10)(11)(12), which is directly linked to severity of lung destruction, propensity for exacerbations, and extent of comorbidities. Thus, we reasoned that probing the molecular basis of WBC regulation and studying the role of hematological CSFs might lead to novel insights into COPD and its comorbidome.…”

A Genome-Wide Association Study in Hispanics/Latinos Identifies Novel Signals for Lung Function. The Hispanic Community Health Study/Study of Latinos

“…One identified a novel variant near MAN2B1 that was associated with percent emphysema on computed tomography (CT) (16) and the other identified two loci that approached genome wide statistical 4 significance for COPD (13). This literature contrasts with that among persons of European ancestry, in whom GWAS have identified multiple loci in genes for lung function and COPD (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) To improve our current understanding of the genetic architecture of lung functionrelated traits in Hispanics/Latinos, we performed a meta-analysis for FEV1, FEV1/FVC, airflow limitation and COPD among six Hispanic/Latino groups in the HCHS/SOL cohort (10,32). Findings were replicated in European, Hispanic and African populations.…”

The smoking gun: Genetics and genomics reveal causal pathways for COPD

“…The NIH maintains an online catalog of GWAS results and as of 12 June 2017, the GWAS Catalog contained 2974 publications and 36,618 unique SNP-trait associations (https://www.ebi.ac.uk/gwas/). The list of traits and diseases, where one or more SNP have achieved the genome-wide threshold for significant association, includes hair color and freckles but also respiratory diseases and phenotypes including Asthma, 7 COPD, 8,9 Lung function, 10 CF disease severity 11 and IPF. 12 As a result, GWAS WORKS!…”

“…Let me remind you that in Dr. Hobbs and Cho's GWAS for COPD SFTPD SNPs were associated with COPD. 9 To see if these SNPs influence surfactant expression, we performed a protein QTL analysis (pQTL). In a pQTL analysis, the effect of SNPs on the expression of a protein is measured instead of mRNA.…”

“…Next, Obeidat and Sin plotted the effect of the SNPs on the risk for COPD in the international COPD Genetics Network cohort 9 versus the effect of the same SNPs on SFTPD serum levels and found that the SNPs that increased SFPD levels the most were associated with the lowest risk for COPD. The same was true in the Lung Health Study cohort; carriers of SNPs that increased SFTPD had a slower decline in lung function over the 5 years of that study.…”