Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA

RationaleAsthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. ObjectivesTo test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations. MethodsThe APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P−8) and three variants reported as suggestive (P−7). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever. Main ResultsWe observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4×10−9). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (PStage1+Stage2 = 1.1x10−9), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (PStage1+Stage2 = 1.1x10−8), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status. ConclusionsPopulation-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.研究背景：哮喘具有较高的发病率与死亡率，且存在较强的遗传基础，但遗传风险因子的鉴定仍受限于合适研究的可及性。研究目的：旨在验证基于人群的队列研究中，经自我报告的医师确诊哮喘患者及全基因组关联分析（Genome-Wide Association, GWA）数据，能否用于验证已知的哮喘相关遗传关联并鉴定新的关联位点。研究方法：APCAT（哮喘性状人群队列分析，Analysis in Population-based Cohorts of Asthma Traits）联盟纳入了来自6个欧洲裔人群队列的1716名哮喘患者与16888名健康对照。我们首先分析了APCAT队列中13个此前已被报道达到全基因组显著性（P < 1×10⁻⁸）的变异，以及3个提示性关联的变异（P < 1×10⁻⁷）。此外，我们在APCAT中开展了全新的关联搜索（阶段1），并在4035名哮喘患者与11251名健康对照中对最具潜力的变异进行了验证（阶段2）。最后，我们首次开展了全基因组水平的基因-吸烟或花粉症交互作用筛查。主要研究结果：所有13个此前已报道的变异均呈现出一致的关联方向，其中10个变异得到了名义上的重复验证。1个此前仅达到提示性关联的变异——位于RORA基因区域的rs11071559，在结合本研究数据后达到了全基因组显著性（P = 2.4×10⁻⁹）。本研究还鉴定出2个全基因组显著性的关联位点：一是位于IL1RL1/IL18R1基因区域附近的rs13408661（阶段1+阶段2合并P = 1.1×10⁻⁹），该变异与近期被证实与哮喘相关的rs3771180存在关联；二是HLA区域内的rs9268516（阶段1+阶段2合并P = 1.1×10⁻⁸），该位点似乎独立于该区域此前已报道的关联信号。最后，我们未发现吸烟或花粉症状态与基因存在显著交互作用的证据。研究结论：采用简单哮喘表型的人群队列，是哮喘遗传学研究中极具价值且尚未被充分开发的研究资源。