Genome-wide gene-by-smoking interaction study of Chronic Obstructive Pulmonary Disease

Risk for Chronic Obstructive Pulmonary Disease (COPD) is determined by both cigarette smoking and genetic susceptibility, but little is known about gene-by-smoking interactions. We performed a genome-wide association analysis of 179,689 controls and 21,077 COPD cases from UK Biobank subjects of European ancestry, considering genetic main effects and gene-by-smoking interaction effects simultaneously (2-degree-of-freedom (2df) test) as well as interaction effects alone (1-degree-of-freedom (1df) interaction test). We sought to replicate significant results in the COPDGene study and SpiroMeta Consortium. We considered two smoking variables: (1) ever/never and (2) current/non-current. In the 1df interaction test, we identified one genome-wide significant locus on 15q25.1 (CHRNB4) and identified PI*Z allele (rs28929474) SERPINA1 and 3q26.2 (MECOM) in an analysis of previously reported COPD loci. In the 2df test, most of the significant signals were also significant for genetic marginal effects, aside from 16q22.1 (SMPD3) and 19q13.2 (EGLN2). The significant effects at 15q25.1 and 19q13.2 loci, both previously described in prior genome-wide association studies of COPD or smoking, but not 16q22.1 or 3q26.2, were replicated in the COPDGene and SpiroMeta. In our study, we identified interaction effects at previously reported COPD loci, however, we failed to identify novel susceptibility loci

Power curves for RITSS1, RITSS2, GESAT, and GAMsv over increasing signal density <i>p</i>_<i>XE</i>.

Significance level α = 0.005, μXE = 0.05, and results based on 1,000 replicates. Power was simulated for pXE = 0.05, 0.1, 0.2, 0.3, 0.4, 0.5.</p

Power curves for RITSS1, RITSS2, GESAT, and GAMsv over increasing signal density <i>p</i>_<i>XE</i>.

Significance level α = 0.005, μXE = 0.1, and results based on 1,000 replicates. Power was simulated for pXE = 0.05, 0.1, 0.2, 0.3, 0.4, 0.5.</p

Analysis configurations and number of genetic variants incorporated.

Analysis configurations and number of genetic variants incorporated.</p

Type 1 error: Quantile-quantile-plots for RITSS1, RITSS2, GESAT, and GAMsv for scenarios 1–5 with SELECT:yes.

All results based on 10,000 replicates. P-values with p−10 were set to p = 10−10. SELECT:yes refers to the scenario where the simulated genetic variants are selected into the analysis based on marginal association p-values.</p

Additional information regarding genetic variants tested in the UK Biobank analysis.

These tables contain all genetic variants as well as the m4/m3 information for the sex-interaction analysis in the UK Biobank. (XLSX)</p

Density plots for standardized residuals for all four traits in the analysis.

FEV1: forced expiratory volume in 1 second, FVC: forced vital capacity. (TIF)</p

Type 1 error: Quantile-quantile-plots for RITSS1, RITSS2, GESAT, and GAMsv for scenarios 1–5 with SELECT:no.

All results based on 10,000 replicates. P-values with p−10 were set to p = 10−10. SELECT:no refers to the scenario where all simulated genetic variants are included in the analysis.</p

Results of the interaction testing using the two approaches RITSS1 and RITSS2 in the UK Biobank.

The environmental factor tested for interaction is denoted by Eit. |m| is the number of total SNPs in the analysis, |m4| and |m3| are the number of SNPs that are shared by all four and exactly three interaction scores, respectively. P-Y-S: pack-years of smoking, E-S: ever-smoking.</p

Visualization of the RITSS algorithm.

Visualization of the RITSS algorithm.</p