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.
SeriesGenetics of chronic obstructive pulmonary disease: understanding the pathobiology and heterogeneity of a complex disorder
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
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)
- et al.
Genetic influences on chronic obstructive pulmonary disease — a twin study
Respir Med
(2010) - et al.
Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis
Lancet Respir Med
(2014) - et al.
Early-onset emphysema in a large French-Canadian family: a genetic investigation
Lancet Respir Med
(2019) - et al.
Genetic susceptibility for chronic bronchitis in chronic obstructive pulmonary disease
Respir Res
(2014) - et al.
Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts
Lancet Respir Med
(2020) - et al.
A functional variant alters binding of activating protein 1 regulating expression of FGF7 gene associated with chronic obstructive pulmonary disease
BMC Med Genet
(2019) - et al.
Behavioral and characterological self-blame in chronic obstructive pulmonary disease
J Psychosom Res
(2012) - et al.
Lung function trajectories in health and disease
Lancet Respir Med
(2019) - et al.
Adult life-course trajectories of lung function and the development of emphysema: the CARDIA Lung Study
Am J Med
(2020) - et al.
Association of clonal hematopoiesis with chronic obstructive pulmonary disease
Blood
(2022)
Global and regional trends in COPD mortality, 1990–2010
Eur Respir J
Quantitative relationships between cigarette smoking and ventilatory function
Am Rev Respir Dis
Smoking and COPD: what really are the risks?
Eur Respir J
Heritability of chronic obstructive pulmonary disease and related phenotypes in smokers
Am J Respir Crit Care Med
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
Meta-analysis of the heritability of human traits based on fifty years of twin studies
Nat Genet
The support of human genetic evidence for approved drug indications
Nat Genet
The COPD genetic association compendium: a comprehensive online database of COPD genetic associations
Hum Mol Genet
Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations
Nat Genet
A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci
PLoS Genet
Variants in FAM13A are associated with chronic obstructive pulmonary disease
Nat Genet
A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13
Hum Mol Genet
Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis
Nat Genet
New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries
Nat Genet
Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function
Nat Commun
karyoploteR: an R/Bioconductor package to plot customizable genomes displaying arbitrary data
Bioinformatics
The genetic architecture of type 2 diabetes
Nature
Biological insights from 108 schizophrenia-associated genetic loci
Nature
Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index
Nat Genet
The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency
Scand J Clin Lab Invest
Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder
J Lab Clin Med
Clinical practice. Alpha1-antitrypsin deficiency
N Engl J Med
New insights into the pathogenesis of autosomal dominant cutis laxa with report of five ELN mutations
Hum Mutat
Abnormalities of the lungs and thoracic cage in the Ehlers-Danlos syndrome
Thorax
Telomerase and the genetics of emphysema susceptibility. Implications for pathogenesis paradigms and patient care
Ann Am Thorac Soc
A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease
Am J Physiol Lung Cell Mol Physiol
Exome sequencing analysis in severe, early-onset chronic obstructive pulmonary disease
Am J Respir Crit Care Med
Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants
Nat Commun
Functional genomics of GPR126 in airway smooth muscle and bronchial epithelial cells
FASEB J
Chronic obstructive pulmonary disease in never-smokers: risk factors, pathogenesis, and implications for prevention and treatment
Lancet Respir Med
Pathogenesis of chronic obstructive pulmonary disease: understanding the contributions of gene–environment interactions across the lifespan
Lancet Respir Med
Evidence for large-scale gene-by-smoking interaction effects on pulmonary function
Int J Epidemiol
Family study of α1-antitrypsin deficiency: effects of cigarette smoking, measured genotype, and their interaction on pulmonary function and biochemical traits
Genet Epidemiol
Genome-wide gene-by-smoking interaction study of chronic obstructive pulmonary disease
Am J Epidemiol
Protective effect of club cell secretory protein (CC-16) on COPD risk and progression: a mendelian randomisation study
Thorax
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
A genome-wide association study of emphysema and airway quantitative imaging phenotypes
Am J Respir Crit Care Med
IREB2 and GALC are associated with pulmonary artery enlargement in chronic obstructive pulmonary disease
Am J Respir Cell Mol Biol
Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis
Am J Respir Crit Care Med
A genetic risk score associated with chronic obstructive pulmonary disease susceptibility and lung structure on computed tomography
Am J Respir Crit Care Med
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