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

https://doi.org/10.1016/S2213-2600(21)00510-5Get rights and content

Summary

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.

Introduction

Chronic obstructive pulmonary disease (COPD) is a leading and rising cause of morbidity and mortality worldwide.1 COPD is usually diagnosed in the setting of exposure to noxious particles or gases, but these exposures incompletely explain disease susceptibility. Cigarette smoking, the most common exposure associated with COPD worldwide, accounts for only a portion of the observed risk.2, 3 Although the health risks of cigarette smoking are incontrovertible, and mitigation of other environmental exposures such as outdoor pollution and indoor biomass fuel use should also be a high priority for public health, other factors are likely to be involved in COPD susceptibility. In fact, genetic risk explains a substantial proportion of the phenotypic variability of COPD.4, 5 Identification of genetic factors associated with COPD might help to explain disease heterogeneity, estimate individual susceptibility, assess prognosis, and identify novel and personalised therapeutics.

In this Series paper, we provide an overview of research into COPD genetics from the past several decades. We review genome-wide association analyses and other genetic studies, and the implications of their findings for our understanding of the genetic risk of COPD. We discuss COPD phenotypes and disease heterogeneity, the ability of genetics to predict COPD risk, the potential role of early-life events in COPD pathogenesis, and specific molecular pathways and targets implicated by genetic studies. We also consider the state of clinical translation and key elements needed to further the impact of genetic studies in understanding and reducing the burden of COPD. A glossary of terms is provided in panel 1.

Section snippets

Genetic epidemiology and COPD

Human DNA is organised in 23 pairs of chromosomes, comprising two copies of approximately 3 billion base pairs that make up the human genome. The differences between any two individuals are small—in the order of one difference per 1000 base pairs, with most of this variation being due to single-nucleotide variants. This genetic variation has an effect on many human diseases and traits.6 Technological advances have made assessment of most single-nucleotide variants in the human genome

Approaches to identify genetic variants in COPD

Initial studies in COPD tested only a few single-nucleotide polymorphisms in or near candidate genes that were thought to have a role in COPD pathogenesis. To a large extent, however, these findings have not been well replicated.9 Although there might still be a role for studying candidate genes with substantial prior evidence, publicly available genome-wide association studies (GWAS)—which have larger sample sizes with greater statistical power, and are currently able to detect variants with

COPD phenotypes and heterogeneity

In addition to discovering new genomic regions associated with COPD, other important lessons have been learned from GWAS. One such lesson relates to phenotypes of COPD. Although post-bronchodilator lung function and cigarette smoke exposure are considered to be key factors for the diagnosis of COPD, most genetic variants identified in GWAS do not seem to be affected substantially by the use of pre-bronchodilator or post-bronchodilator spirometry, or by the inclusion of adults with asthma or

Combined effect of genetic variants

A second important insight from COPD genetic studies is the effect of genetic variation on disease risk. For mendelian diseases such as severe α1-antitrypsin deficiency and cystic fibrosis, a single genetic variant is responsible for a markedly elevated risk of disease. GWAS in COPD have identified risk variants with odds ratios of approximately 1·3 or less, and thus individual variants poorly predict risk. Combining multiple genome-wide significant variants into a genetic risk score and, more

Clinical and translational implications

What are the clinical and translational implications of the reported findings in COPD genetics? Simply understanding that a substantial portion of COPD susceptibility comes from genetic factors and early-life events might help to mitigate the detrimental effects of self-blame that is common in COPD.81 Our understanding of the genetic effects on specific phenotypes has also changed. Most identified COPD genetic susceptibility loci overlap with genetic susceptibility to reduced pre-bronchodilator

Future directions in COPD genetics

Despite tremendous advances in COPD genetics over the past few decades, the field is still in its infancy. The first GWAS was reported just over a decade ago, and whole-genome sequencing data have only recently become available. The fraction of genetic risk (or heritability) that is explained by COPD genetic loci with evidence of replication is only about 10% in people of European ancestry10, 16 and even less so in other populations. This missing heritability is probably due to other, mostly

Search strategy and selection criteria

We searched PubMed using the search term “COPD” [MeSH] in combination with the term “genetic association study” [MeSH] for papers published in English from database inception to Oct 9, 2021, and in combination with the search term “genetic*” [MeSH] for papers published in English from Jan 1, 2015, to Oct 9, 2021. We focused on human studies, and the final list of cited articles was selected on the basis of their relevance to the aims of this Series paper.

Declaration of interests

MHC and EKS have received grant support from GlaxoSmithKline and Bayer. MHC has received consulting and speaking fees from Illumina and AstraZeneca. BDH declares no competing interests.

References (112)

  • PG Burney et al.

    Global and regional trends in COPD mortality, 1990–2010

    Eur Respir J

    (2015)
  • B Burrows et al.

    Quantitative relationships between cigarette smoking and ventilatory function

    Am Rev Respir Dis

    (1977)
  • S Marsh et al.

    Smoking and COPD: what really are the risks?

    Eur Respir J

    (2006)
  • JJ Zhou et al.

    Heritability of chronic obstructive pulmonary disease and related phenotypes in smokers

    Am J Respir Crit Care Med

    (2013)
  • EK Silverman et al.

    Genetic epidemiology of severe, early-onset chronic obstructive pulmonary disease. Risk to relatives for airflow obstruction and chronic bronchitis

    Am J Respir Crit Care Med

    (1998)
  • TJC Polderman et al.

    Meta-analysis of the heritability of human traits based on fifty years of twin studies

    Nat Genet

    (2015)
  • MR Nelson et al.

    The support of human genetic evidence for approved drug indications

    Nat Genet

    (2015)
  • PJ Castaldi et al.

    The COPD genetic association compendium: a comprehensive online database of COPD genetic associations

    Hum Mol Genet

    (2010)
  • P Sakornsakolpat et al.

    Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations

    Nat Genet

    (2019)
  • SG Pillai et al.

    A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci

    PLoS Genet

    (2009)
  • MH Cho et al.

    Variants in FAM13A are associated with chronic obstructive pulmonary disease

    Nat Genet

    (2010)
  • MH Cho et al.

    A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13

    Hum Mol Genet

    (2012)
  • BD Hobbs et al.

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

    Nat Genet

    (2017)
  • N Shrine et al.

    New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries

    Nat Genet

    (2019)
  • AB Wyss et al.

    Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

    Nat Commun

    (2018)
  • B Gel et al.

    karyoploteR: an R/Bioconductor package to plot customizable genomes displaying arbitrary data

    Bioinformatics

    (2017)
  • C Fuchsberger et al.

    The genetic architecture of type 2 diabetes

    Nature

    (2016)
  • Biological insights from 108 schizophrenia-associated genetic loci

    Nature

    (2014)
  • J Yang et al.

    Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index

    Nat Genet

    (2015)
  • C-B Laurell et al.

    The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency

    Scand J Clin Lab Invest

    (1963)
  • HL Sharp et al.

    Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder

    J Lab Clin Med

    (1969)
  • EK Silverman et al.

    Clinical practice. Alpha1-antitrypsin deficiency

    N Engl J Med

    (2009)
  • B Callewaert et al.

    New insights into the pathogenesis of autosomal dominant cutis laxa with report of five ELN mutations

    Hum Mutat

    (2011)
  • JG Ayres et al.

    Abnormalities of the lungs and thoracic cage in the Ehlers-Danlos syndrome

    Thorax

    (1985)
  • SE Stanley et al.

    Telomerase and the genetics of emphysema susceptibility. Implications for pathogenesis paradigms and patient care

    Ann Am Thorac Soc

    (2016)
  • M Moll et al.

    A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease

    Am J Physiol Lung Cell Mol Physiol

    (2021)
  • D Qiao et al.

    Exome sequencing analysis in severe, early-onset chronic obstructive pulmonary disease

    Am J Respir Crit Care Med

    (2016)
  • X Zhao et al.

    Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants

    Nat Commun

    (2020)
  • RJ Hall et al.

    Functional genomics of GPR126 in airway smooth muscle and bronchial epithelial cells

    FASEB J

    (2021)
  • IA Yang et al.

    Chronic obstructive pulmonary disease in never-smokers: risk factors, pathogenesis, and implications for prevention and treatment

    Lancet Respir Med

    (2022)
  • A Agustí et al.

    Pathogenesis of chronic obstructive pulmonary disease: understanding the contributions of gene–environment interactions across the lifespan

    Lancet Respir Med

    (2022)
  • H Aschard et al.

    Evidence for large-scale gene-by-smoking interaction effects on pulmonary function

    Int J Epidemiol

    (2017)
  • EK Silverman et al.

    Family study of α1-antitrypsin deficiency: effects of cigarette smoking, measured genotype, and their interaction on pulmonary function and biochemical traits

    Genet Epidemiol

    (1992)
  • W Kim et al.

    Genome-wide gene-by-smoking interaction study of chronic obstructive pulmonary disease

    Am J Epidemiol

    (2021)
  • S Milne et al.

    Protective effect of club cell secretory protein (CC-16) on COPD risk and progression: a mendelian randomisation study

    Thorax

    (2020)
  • A Manichaikul et al.

    Genome-wide study of percent emphysema on computed tomography in the general population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study

    Am J Respir Crit Care Med

    (2014)
  • MH Cho et al.

    A genome-wide association study of emphysema and airway quantitative imaging phenotypes

    Am J Respir Crit Care Med

    (2015)
  • JH Lee et al.

    IREB2 and GALC are associated with pulmonary artery enlargement in chronic obstructive pulmonary disease

    Am J Respir Cell Mol Biol

    (2015)
  • RJ Allen et al.

    Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

    Am J Respir Crit Care Med

    (2020)
  • EC Oelsner et al.

    A genetic risk score associated with chronic obstructive pulmonary disease susceptibility and lung structure on computed tomography

    Am J Respir Crit Care Med

    (2019)
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