• Brian D Hobbs, Margaret M Parker, Han Chen, Taotao Lao, Megan Hardin, Dandi Qiao, Iwona Hawrylkiewicz, Pawel Sliwinski, Jae-Joon Yim, Woo Jin Kim, Deog Kyeom Kim, Peter J Castaldi, Craig P Hersh, Jarrett Morrow, Bartolome R Celli, Victor M Pinto-Plata, Gerald J Criner, Nathaniel Marchetti, Raphael Bueno, Alvar Agustí, Barry J Make, James D Crapo, Peter M Calverley, Claudio F Donner, David A Lomas, Emiel F M Wouters, Jorgen Vestbo, Peter D Paré, Robert D Levy, Stephen I Rennard, Xiaobo Zhou, Nan M Laird, Xihong Lin, Terri H Beaty, Edwin K Silverman, Michael H Cho, NETT Genetics Investigators, ECLIPSE Investigators, COPDGene Investigators, and International COPD Genetics Network Investigators.
• 1 Channing Division of Network Medicine.
• Am. J. Respir. Crit. Care Med. 2016 Jul 1; 194 (1): 485748-57.

RationaleChronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome-wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility.ObjectivesTo identify coding variants associated with COPD.MethodsWe tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts.Measurements And Main ResultsWe included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 × 10(-14)) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 × 10(-6)) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 × 10(-8)) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM.ConclusionsIn an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis.

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