While the effect of an individual genetic variant may be small, discounting small effects in GWAS as unimportant would have ignored such critical effects as the insulin gene (INS) in diabetes and the HMG-CoA reductase gene (HMGCR) in cholesterol metabolism106,107; more dramatic perturbations of these causal genes – through experimental disruption76 or through identification of rare, more deleterious genetic variants108 – can highlight the importance of pathophysiology identified by GWAS. In addition, cumulative effects of these loci may be substantial. Although more accurate risk prediction estimates will require assessments in independent populations, the increased odds of 1·24 with each COPD GWAS risk allele in the COPDGene population suggest that harboring three risk alleles could nearly double odds of moderate to severe COPD. By comparison, the population-based BOLD study109 estimated an odds ratio for COPD per ten pack-years of smoking from1•16 to 1•28. These data, together with previous studies of familial aggregation and heritability of COPD, highlight the importance of genetic risk factors apart from alpha-1 antitrypsin deficiency in increasing risk of COPD.
