Role of Lung Function Genes in the Development of Asthma

Although our previous GWAS failed to identify SNPs associated with pulmonary function at the level of genomewide significance, it did show that the heritability for FEV(1)/FVC was 41.6% in a Japanese population, suggesting that the heritability of pulmonary function traits can be explained by the additive effects of multiple common SNPs. In addition, our previous study indicated that pulmonary function genes identified in previous GWASs in non-Japanese populations accounted for 4.3% to 12.0% of the entire estimated heritability of FEV(1)/FVC in a Japanese population. Therefore, given that many loci with individual weak effects may contribute to asthma risk, in this study, we created a quantitative score of genetic load based on 16 SNPs implicated in lower lung function in both Japanese and non-Japanese populations. This genetic risk score (GRS) for lower FEV(1)/FVC was consistently associated with the onset of asthma (P = 9.6 × 10(−4)) in 2 independent Japanese populations as well as with the onset of COPD (P = 0.042). Clustering of asthma patients based on GRS levels indicated that an increased GRS may be responsible for the development of a particular phenotype of asthma characterized by early onset, atopy, and severer airflow obstruction.