Genetic Advances in Chronic Obstructive Pulmonary Disease. Insights from COPDGene

Abstract

Chronic obstructive pulmonary disease (COPD) is a common and progressive disease that is influenced by both genetic and environmental factors. For many years, knowledge of the genetic basis of COPD was limited to Mendelian syndromes, such as alpha-1 antitrypsin deficiency and cutis laxa, caused by rare genetic variants. Over the past decade, the proliferation of genome-wide association studies, the accessibility of whole-genome sequencing, and the development of novel methods for analyzing genetic variation data have led to a substantial increase in the understanding of genetic variants that play a role in COPD susceptibility and COPD-related phenotypes. COPDGene (Genetic Epidemiology of COPD), a multicenter, longitudinal study of over 10,000 current and former cigarette smokers, has been pivotal to these breakthroughs in understanding the genetic basis of COPD. To date, over 20 genetic loci have been convincingly associated with COPD affection status, with additional loci demonstrating association with COPD-related phenotypes such as emphysema, chronic bronchitis, and hypoxemia. In this review, we discuss the contributions of the COPDGene study to the discovery of these genetic associations as well as the ongoing genetic investigations of COPD subtypes, protein biomarkers, and post-genome-wide association study analysis.

Keywords: chronic obstructive pulmonary disease; epidemiology; genetics.

Figure 1.

Manhattan plot of chronic obstructive pulmonary disease genome-wide association study by the International COPD Genetics Consortium. The dashed line corresponds to the threshold for genome-wide statistical significance (P < 5 × 10⁻⁸). Reprinted by permission from Reference .

Figure 2.

Summary phenogram plot of genome-wide association studies for chronic obstructive pulmonary disease (COPD) susceptibility and COPD-related phenotypes reviewed in this article. Individual SNP associations have been collapsed into the nearest gene or locus where genes are densely clustered. Although multiple SNP associations may be reported in an individual locus for a given phenotype, only one association is depicted. COPD susceptibility associations (blue) include all 22 loci reported by Hobbs and colleagues (18). Lung function (FEV₁, FVC, and FEV₁/FVC) associations depicted here (red) include associations from the comprehensive study conducted by Wain and colleagues (19). BDR = bronchodilator response; BMI = body mass index; CB = chronic bronchitis; EMPH.DIST.RATIO = emphysema distribution ratio of upper divided by lower lung fields; FFMI = fat-free mass index; LAA.950 = percentage of lung density histogram below −950 Hounsfield units; LHE = local histogram–based emphysema; MOD = moderate centrilobular emphysema on local histogram–based emphysema analysis; NORM = normal/nonemphysematous on local histogram–based emphysema analysis; OS = resting oxygen saturation; PAE = pulmonary artery enlargement; PAN = panlobular emphysema on local histogram–based emphysema analysis; PB = post-bronchodilator; PCT.GAS = percent gas trapping at −856 Hounsfield units on expiratory computed tomographic scan; PERC15 = 15th percentile point of the lung density histogram; SEV = severe centrilobular emphysema on local histogram–based emphysema analysis; VIS.EMPH = visual emphysema (presence/absence).

Figure 3.

Many novel genome-wide associations between SNPs and blood protein biomarkers were found. Combined Manhattan plots show SNPs associated with blood protein levels quantitative trait loci (pQTL) by chromosomal location for 38 biomarkers with at least one SNP significant at genome-wide significance after adjustment for multiple testing (red line). The −log₁₀ P values are shown using results from a meta-analysis of both SPIROMICS and COPDGene SNPs. More than 300 novel pQTLs were identified. COPD = chronic obstructive pulmonary disease; COPDGene = Genetic Epidemiology of COPD; SPIROMICS = Subpopulations and Intermediate Outcome Measures in COPD Study. Reprinted by permission from Reference .