Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide(1). We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 x 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples(2-7), while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis(8,9) (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity(10). We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases

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.…”

Genetic studies as a tool for identifying novel potential targets for treatment of COPD

“…Over the past decade, GWAS by the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) [7] and SpiroMeta consortia [8] have identified ~30 gene regions that contain common single nucleotide polymorphisms (SNPs) significantly associated with Forced Expiratory Volume in 1 second (FEV 1 ) and its ratio to Forced Vital Capacity (FEV 1 /FVC). GWAS approaches have also been used to identify genetic variants for COPD [5, 9–13]. Major candidate gene regions identified through GWAS of COPD include FAM13A [11], CHRNA3/5/IREB2 [9], and HHIP [13], with four novel loci, EEFSEC , DSP , MTCL1 , and SFTPD , that emerged in the most recently published GWAS of COPD [5].…”

“…In this issue of the European Respiratory Journal , Obeidat et al [4] identify surfactant protein-D (SP-D) as a potentially causal risk factor for COPD. The paper is presented in multiple distinct parts, beginning with a genome-wide association study to identify SNPs from three genomic regions (on chromosomes 6, 10 and 16) associated with circulating levels of SP-D, followed by a Mendelian Randomization study demonstrating that genetically determined lower levels of SP-D are associated with increased risk of COPD based on results from a large-scale consortium based on a Genome-wide association study (GWAS) of up to ~11,000 COPD cases and ~37,000 controls recently published by the International COPD Genetics Consortium (ICGC) [5]. The results from the study of Obeidat et al [4] are promising and open new potential avenues for early diagnosis and treatment of this disease.…”

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

“…I will return to these later in the talk. A recent large GWAS for COPD published by Hobbs and associates 8 revealed a similar number of "hits"; 22 independent loci, 13 of which overlapped with the lung function-related susceptibility genes ( Figure 7). Again, no obvious biological pathways were evident, but HHIP was the most significant hit, and a lung protein Surfactant Protein D achieved the genome wide threshold; I will return to it as well.…”

“…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!…”