Department of Mathematics and Statistics, Old Dominion University, Norfolk, Virginia, USA.
Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina, USA.
Thorax. 2021 Dec;76(12):1219-1226. doi: 10.1136/thoraxjnl-2020-215624. Epub 2021 May 7.
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.
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, FVC and FEV/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) genetic variants, after clumping based on distance (±250 kb) and linkage disequilibrium (r=0.5). We used linear regression, adjusting for relevant covariates, to estimate associations of each trait with its GRS and to assess interactions.
Each trait was highly significantly associated with its GRS (all three p values<8.9×10). The inverse association of the GRS with FEV/FVC was stronger for current smokers (p=0.017) or former smokers (p=0.064) when compared with never smokers and among asthmatics compared with non-asthmatics (p=0.053). No significant interactions were observed between any GRS and house dust endotoxin.
Evaluation of interactions using GRSs supports a greater impact of increased genetic susceptibility on reduced pulmonary function in the presence of smoking or asthma.
全基因组关联研究（GWAS）已经确定了许多与较低肺功能相关的基因座。肺功能与吸烟密切相关，也与哮喘和尘螨内毒素有关。在个体 SNP 水平上，全基因组肺功能分析尚未发现明显的基因-环境相互作用证据。遗传风险评分（GRS）可以提高识别基因-环境相互作用的能力，但研究较少。
我们分析了 2844 名欧洲血统个体，这些个体来自美国农业队列中嵌套的成人哮喘病例对照研究的 1000 基因组 GWAS 数据。肺功能特征为 FEV、FVC 和 FEV/FVC。利用最近一项大型 GWAS 荟萃分析的数据，我们通过结合每个特征的 top（p 值<5×10）遗传变异，构建了加权 GRS，这些变异基于距离（±250 kb）和连锁不平衡（r=0.5）进行聚类。我们使用线性回归，调整了相关协变量，以估计每个特征与 GRS 的关联，并评估相互作用。
每个特征都与 GRS 高度显著相关（三个特征的 p 值均<8.9×10）。与从不吸烟者相比，当前吸烟者（p=0.017）或前吸烟者（p=0.064）的 GRS 与 FEV/FVC 的逆关联更强，与非哮喘者相比，哮喘者的 GRS 与 FEV/FVC 的逆关联更强（p=0.053）。未观察到任何 GRS 与室内灰尘内毒素之间存在显著相互作用。
使用 GRS 评估相互作用表明，在吸烟或哮喘存在的情况下，增加遗传易感性对降低肺功能的影响更大。
