Interaction between Genetic Risk Scores for reduced pulmonary function and smoking, asthma and endotoxin

RATIONALE: Genome-wide association studies (GWASs) have identified numerous loci associated with lower pulmonary function. Pulmonary function is strongly related to smoking and has also been associated with asthma and dust endotoxin. At the individual SNP level, genome-wide analyses of pulmonary function have not identified appreciable evidence for gene by environment interactions. Genetic Risk Scores (GRSs) may enhance power to identify gene–environment interactions, but studies are few. METHODS: We analysed 2844 individuals of European ancestry with 1000 Genomes imputed GWAS data from a case–control study of adult asthma nested within a US agricultural cohort. Pulmonary function traits were FEV(1), FVC and FEV(1)/FVC. Using data from a recent large meta-analysis of GWAS, we constructed a weighted GRS for each trait by combining the top (p value<5×10(−9)) genetic variants, after clumping based on distance (±250 kb) and linkage disequilibrium (r(2)=0.5). We used linear regression, adjusting for relevant covariates, to estimate associations of each trait with its GRS and to assess interactions. RESULTS: Each trait was highly significantly associated with its GRS (all three p values<8.9×10(−8)). The inverse association of the GRS with FEV(1)/FVC was stronger for current smokers (p(interaction)=0.017) or former smokers (p(interaction)=0.064) when compared with never smokers and among asthmatics compared with non-asthmatics (p(interaction)=0.053). No significant interactions were observed between any GRS and house dust endotoxin. CONCLUSIONS: Evaluation of interactions using GRSs supports a greater impact of increased genetic susceptibility on reduced pulmonary function in the presence of smoking or asthma.