Background
Although studies have identified hundreds of genetic variants associated with asthma risk, a large fraction of heritability remains unexplained, especially in Chinese individuals.
Methods
To identify genetic risk factors for asthma in a Han Chinese population, 211 asthma‐related genes were first selected based on database searches. The genes were then sequenced for subjects in a Discovery Cohort (284 asthma patients and 205 older healthy controls) using targeted next‐generation sequencing. Bioinformatics analysis and statistical association analyses were performed to reveal the associations between rare/common variants and asthma, respectively. The identified common risk variants underwent a validation analysis using a Replication Cohort (664 patients and 650 controls).
Results
First, we identified 18 potentially functional rare loss‐of‐function (LOF) variants in 21/284 (7.4%) of the asthma cases. Second, using burden tests, we found that the asthma group had nominally significant (p < 0.05) burdens of rare nonsynonymous variants in 10 genes. Third, 23 common single‐nucleotide polymorphisms were associated with the risk of asthma, 7/23 (30.4%) and 9/23 (39.1%) of which were modestly significant (p < 9.1 × 10−4) in the Replication Cohort and Combined Cohort, respectively. According to our cumulative risk model involving the modestly associated alleles, middle‐ and high‐risk subjects had a 2.0‐fold (95% CI: 1.621–2.423, p = 2.624 × 10−11) and 6.0‐fold (95% CI: 3.623–10.156, p = 7.086 × 10−12) increased risk of asthma, respectively, compared with low‐risk subjects.
Conclusion
This study revealed novel rare and common genetic risk factors for asthma, and provided a cumulative risk model for asthma risk prediction and stratification in Han Chinese individuals.