We describe six new signals of association with FEV1 extremes, all of which were also associated with COPD using our definition based on spirometry. Five of these signals were most strongly associated with extremes of FEV1 (low vs high) in never smokers. The signal at 17q21.31 for extremes of FEV1 suggests a role for structural variation and epigenetic regulation in lung health. We found that the number of copies of the 5′ end of KANSL1—a gene disrupted by duplication events—is associated with FEV1 extremes. KANSL1 encodes a protein that is a key component of the NSL1 (histone acetyltransferase) complex.50 The disruption of the gene gives rise to a novel truncated transcript,42 which encodes a protein missing a domain essential for key interactions with other proteins important for NSL1 function.51 Therefore, widespread effects on gene regulation through altered histone acetylation could underlie this association. Reduced expression of KANSL1 causes a rare multisystem disorder,52,53 suggesting an essential role for KANSL1 in epigenetic regulation. In a genome-wide pathway analysis, we identified the histone gene set, further implicating a role for epigenetic regulation in lung health.
