The 19q13 locus did not achieve genome-wide significant in this study, despite being identified in our prior meta-analysis in the ECLIPSE, NETT/NAS, Norway (GenKOLS), and the initial 1000 non-Hispanic White subjects from the COPDGene study7. In the current analysis of moderate-to-severe disease, rs7937 (nearest gene, RAB4B) was just below genome-wide significance (6•2×10−); however, the association was genome-wide significant (1•0×10−9) in a model adjusting only for principal components of genetic ancestry, and more significant when limited to non-Hispanic whites. A recent study in a Japanese population confirmed an association with smoking behavior with SNPs in this region78, and additional analyses of nicotine addiction and lung eQTLs suggest effects at this locus may be mediated through several different variants in CYP2A6 as well as EGLN2 79–81. Together, these data suggest effects of the 19q13 locus on COPD act through a mechanism involving cigarette smoking, and are complex, potentially in the presence of locus heterogeneity across populations.
