Genetics of chronic obstructive pulmonary disease: understanding the pathobiology and heterogeneity of a complex disorder

Abstract

Chronic obstructive pulmonary disease (COPD) is a deadly and highly morbid disease. Susceptibility to and heterogeneity of COPD are incompletely explained by environmental factors such as cigarette smoking. Family-based and population-based studies have shown that a substantial proportion of COPD risk is related to genetic variation. Genetic association studies have identified hundreds of genetic variants that affect risk for COPD, decreased lung function, and other COPD-related traits. These genetic variants are associated with other pulmonary and non-pulmonary traits, demonstrate a genetic basis for at least part of COPD heterogeneity, have a substantial effect on COPD risk in aggregate, implicate early-life events in COPD pathogenesis, and often involve genes not previously suspected to have a role in COPD. Additional progress will require larger genetic studies with more ancestral diversity, improved profiling of rare variants, and better statistical methods. Through integration of genetic data with other omics data and comprehensive COPD phenotypes, as well as functional description of causal mechanisms for genetic risk variants, COPD genetics will continue to inform novel approaches to understanding the pathobiology of COPD and developing new strategies for management and treatment.

Figure 1:

Karyogram of GWAS associations for COPD and related lung function phenotypes (FEV₁ and FEV₁/FVC)(11,12,105). Regions within 1 megabase were combined, and one gene name chosen to represent the region.

Figure 2:

Multiple phenotypic effects identified at COPD and lung function genetic loci. A) Association of 279 lung function variants with 2,411 traits in UK Biobank(12), demonstrating extensive pleiotropy B) Hierarchical clustering of COPD genetic loci with chest imaging phenotypes in COPDGene(11). Variants clustered by association with airway features or emphysema features, suggesting that different groups of genetic variants may explain imaging heterogeneity in COPD.

Figure 3:

Odds ratios for COPD by decile of a polygenetic risk score(40).

Figure 4:

Genetic association with COPD or a COPD related phenotype, ideally with replication, can be done through standard genome-wide association studies for common variants, sequencing and rare variant based studies. Once an association is identified, efforts should be made to identify the likely causal variant(s) through a procedure called ‘fine mapping’, since linkage disequilibrium results in extensive correlation of variants through the genome. For rare protein altering variants, there may be no other likely causal variants; for intragenic regions with high linkage disequilibrium, there may be hundreds or more potential causal variants. Identifying a causal gene for regulatory variants (the majority of variants found by GWAS) is challenging: variant (or SNP) to gene strategies include molecular QTL (e.g. expression QTL, or eQTL) analysis ideally with colocalization, identification of open chromatin regions that correlate with gene expression, usually in specific cell types. ‘Functional genetics’ encompasses a set of experimental approaches to test the perturbation of an individual variant, regulatory region, or gene, in a specific cell type, organoid, or organism model, consistent with a hypothesis generated from downstream genetic analyses. GWAS or association studies alone are sufficient to generate genetic risk scores, or in the case of variant(s) of large effect or affecting one pathway, a disease subtype (e.g. alpha-1 antitrypsin deficiency), though fine mapping and other methods may help improve these scores. To identify novel drug pathways and therapeutic targets, there should be an understanding of the basic effector gene and cell types, ideally after functional genetics assays.