The analysis of severe COPD reduced the number of cases to 3,497, while the number of controls remained the same. Baseline characteristics of the severe subsets of COPDGene, ECLIPSE, and GenKOLS (Norway) cases are shown in Table 2 (characteristics of NETT subjects are included in Table 1, as all NETT cases are severe). Similarly to the analysis of moderate-to-severe cases, we found no evidence of inflation due to population stratification (individual λGC ≤ 1.04; overall λGC = 1•04; λGC1000 = 1•01, Figure S2) among severe cases and controls. We again confirmed the three previously described COPD loci: 4q22 (FAM13A), 15q25 (CHRNA3/5/IREB2), and 4q31 (HHIP) – as genome-wide significant for severe COPD (Table 4 and Figure 2). We noted effect estimates for these loci tended to be larger in severe COPD than in moderate to severe COPD cases; these differences were statistically significant at two markers (P < 0•01 for rs13141641 (15q25), and rs12914385, (HHIP)), and just above statistical significance for a third (P = 0•08 for rs4416442 (FAM13A)).
