Our study does not address other genetic contributors to COPD susceptibility. We did not, for example, consider gene-gene interactions or gene-environment interaction. The genotyping and imputation in this study are not well-suited to address the role of rare variants, which may also be important in explaining COPD susceptibility95–97. Our definition of cases and controls was based only on the presence of moderate, or moderate-to-severe airflow obstruction, yet COPD is highly heterogeneous. Analysis of individual characteristics (e.g. emphysema) or of specific subtypes (e.g. severe disease, as we demonstrate here; radiographically defined subsets; or separate GOLD categories2,98) may provide greater insight into the development of this complex and heterogeneous disease27–30. Well-powered studies of lung function in the general population, as well as COPD ascertained through population-based studies, have not identified several of the loci reported here22,56,99–101. Additional studies will be helpful in determining whether heterogeneity in COPD definitions, including varying degrees of severity and case ascertainment, differential effects of genetic variants in disease versus lung function in the general population, or Type 1 or Type 2 error could account for these discrepancies.
