shown that this leads to minimal misclassification of moderate-severe (GOLD 2-4) COPD43. The effect size estimates for COPD associations could be influenced by differences in case ascertainment between the follow-up studies. Motivated by avoidance of potential winner’s curse bias for the 48 variants discovered using UK BiLEVE, we excluded UK BiLEVE from individual variant analyses. However, this excluded 9,563 moderate to severe COPD cases, and therefore the significance of COPD association tests for these variants should be interpreted with caution. Notably, we found effect size estimates only slightly smaller in deeply-characterised COPD case-control studies than in UK Biobank (OR per SD change in allelic risk score 1.36 compared to 1.42). Whilst we show an appreciable proportion of COPD cases could be attributable to allelic risk scores above the first decile, great caution must be exercised in interpretation of population attributable risk fraction estimates given considerations of shared etiologic responsibility44. The lung function-associated variants we report were not associated with acute exacerbations of COPD. Although more powerful studies of exacerbations will be required, this suggests that different genetic mechanisms could underlie risk of acute exacerbations.
