Genome-Wide Gene-by-Smoking Interaction Study of Chronic Obstructive Pulmonary Disease

Abstract

Risk of 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 recruited from 2006 to 2010, considering genetic main effects and gene-by-smoking interaction effects simultaneously (2-degrees-of-freedom (df) test) as well as interaction effects alone (1-df interaction test). We sought to replicate significant results in COPDGene (United States, 2008-2010) and SpiroMeta Consortium (multiple countries, 1947-2015) data. We considered 2 smoking variables: 1) ever/never and 2) current/noncurrent. In the 1-df test, we identified 1 genome-wide significant locus on 15q25.1 (cholinergic receptor nicotinic β4 subunit, or CHRNB4) for ever- and current smoking and identified PI*Z allele (rs28929474) of serpin family A member 1 (SERPINA1) for ever-smoking and 3q26.2 (MDS1 and EVI1 complex locus, or MECOM) for current smoking in an analysis of previously reported COPD loci. In the 2-df test, most of the significant signals were also significant for genetic marginal effects, aside from 16q22.1 (sphingomyelin phosphodiesterase 3, or SMPD3) and 19q13.2 (Egl-9 family hypoxia inducible factor 2, or EGLN2). The significant effects at 15q25.1 and 19q13.2 loci, both previously described in prior genome-wide association studies of COPD or smoking, were replicated in COPDGene and SpiroMeta. We identified interaction effects at previously reported COPD loci; however, we failed to identify novel susceptibility loci.

Keywords: chronic obstructive pulmonary disease; gene-by-smoking interaction; gene-environment interaction; genome-wide association study; smoking.

Figure 1

Analysis workflow for a genome-wide gene-by-smoking interaction analysis conducted in UK Biobank subjects, United Kingdom, 2006–2010. In the genome-wide scan, the genome-wide significance was set at P < 5.00 × 10⁻⁸. In the candidate variants, the significance threshold was considered as Bonferroni significance (P < 1.00 × 10⁻⁴). Candidate variants were selected from genome-wide association study of COPD (5) and lung function (15) and previously reported gene-by-smoking interactions of chronic obstructive pulmonary disease (1, 2, 4). Significant findings in the genome-wide scan and in candidate variants were selected to replicate in COPDGene (United States, 2008–2010) (14) and SpiroMeta consortium (multiple countries, 1947–2015) (15). CHRNB4, cholinergic receptor nicotinic β4 subunit; df, degrees of freedom; EGLN2, Egl-9 family hypoxia inducible factor 2; MECOM, myelodysplastic syndrome 1 and ecotropic viral integration site 1 complex locus; SERPINA1, serpin family A member 1; SMPD3, sphingomyelin phosphodiesterase 3.

Figure 2

Statistical significances of selected variants in multiple data sets. A) Variants presenting main effects based on the 2-degrees-of-freedom (df) joint test. Smoking exposures of rs141322661 and rs2604894 are ever-smoking and current smoking, respectively. B) Variants presenting the evidence of interaction effects based on the 1-df interaction test. Smoking exposures of rs7642001, rs28929474, and rs12440014 are current smoking, ever-smoking, and ever-smoking, respectively. For selected variants presenting the genome-wide significance from a 2-df joint test and a 1-df interaction test in the genome-wide gene-by-smoking interaction analysis, we compared the P values for a marginal genome-wide association study of chronic obstructive pulmonary disease (5) (marginal genome-wide association study (GWAS)), stratified analysis of marginal GWAS by smoking exposure (exposed and unexposed), 1-df interaction test and 2-df joint test. Summary statistics of “Marginal GWAS” are from the meta-analysis of UK Biobank (2006–2010) and the International COPD Genetics Consortium (multiple countries, 1987–2013) (5). Summary statistics of analysis testing of “Exposed,” “Unexposed,” “1-df Interaction,” and “2-df Joint” are from the analysis of UK Biobank (2006–2010).