Exome Array Analysis of Chronic Obstructive Pulmonary Disease

Background: Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have focused on common variation, but rare coding variants are known to affect COPD susceptibility. We hypothesized that an exome array analysis would identify single non-synonymous variants and gene-based aggregates of non-synonymous variants associated with COPD. Methods: We used the Illumina HumanExome array to genotype individuals in six COPD cohorts: Caucasian subjects from the family-based Boston Early-Onset COPD Study (BEOCOPD) and International COPD Genetics Network (ICGN), and the case-control COPDGene (non-Hispanic whites and African-Americans) and Transcontinental COPD Genetics Study (Poland and Korea). Cases were defined as GOLD Grade 2 and above COPD. Controls had normal lung function; the vast majority were current or former smokers. We tested single non-synonymous, stop and splice variants with a minor allele frequency (MAF) of > 0.5% in an additive model using logistic regression and combined results in a fixed-effects meta-analysis. Our gene-based testing was performed on non-synonymous, stop, and splice variants with MAF < 5% and used SKAT-O with meta-analysis in the MetaSKAT software in R. We performed meta-analyses for all subjects and separately by ethnicity. We adjusted all analyses for age, sex, pack-years of smoking, and ancestry-related principal components. Exome-wide significance was determined to be 2.3x10-6 for single variant testing and 4.1x10-6 for gene-based testing. Results: Across the six cohorts, we included 5971 controls and 6054 cases in our analysis. We identified an exome-wide significant non-synonymous variant rs16969968 (p=1.4x10-13) in CHRNA5 at a locus previously described in association with COPD susceptibility and nicotine addiction. No additional variants or genes met exome-wide significance. Additional top association results included variants in MMP3, AGER, and SERPINA1. A non-synonymous variant in IL27 (p=5.6x10-6) was just below the level of exome-wide significance. In gene-based testing, the top gene was CYB5RL with p=3.9x10-5. We also identified several non-synonymous SNPs at previously described GWAS loci for COPD or lung function, including GPR126, RIN3, MECOM, and TNS1. Conclusions: We have performed an exome array analysis for COPD in multiple populations. Although no novel variants or genes were identified at exome-wide significance, our analysis confirms associations at previously discovered loci and identifies coding variants for potential future study. Additionally, we identified a variant in IL27 just below the significance threshold as a potential candidate for COPD pathogenesis.