Genome-wide association studies (GWASs) have identified dozens of loci associated with risk of chronic obstructive pulmonary disease (COPD). However, identifying the causal variants and their functional role in the appropriate cell type remains a major challenge. We aimed to identify putative causal variants in 82 GWAS loci associated with COPD susceptibility and predict the regulatory impact of these variants in lung-cell types. We used an integrated approach featuring statistical fine mapping, open chromatin profiling, and machine learning to identify functional variants. We generated chromatin accessibility data using the Assay for Transposase-Accessible Chromatin with High-Throughput Sequencing (ATAC-seq) for human primary lung-cell types implicated in COPD pathobiology. We then evaluated the enrichment of COPD risk variants in lung-specific open chromatin regions and generated cell type–specific regulatory predictions for >6,500 variants corresponding to 82 COPD GWAS loci. Integration of the fine-mapped variants with lung open chromatin regions helped prioritize 22 variants in putative regulatory elements with potential functional effects. Comparison with functional predictions from 222 Encyclopedia of DNA Elements (ENCODE) cell samples revealed cell type–specific regulatory effects of COPD variants in the lung epithelium, endothelium, and immune cells. We identified potential causal variants for COPD risk by integrating fine mapping in GWAS loci with cell-specific regulatory profiling, highlighting the importance of leveraging the chromatin status in relevant cell types to predict the molecular effects of risk variants in lung disease.

全基因组关联研究 (GWAS) 已经确定了数十个与慢性阻塞性肺病 (COPD) 风险相关的位点。然而，确定因果变异及其在适当细胞类型中的功能作用仍然是一个重大挑战。我们旨在确定与 COPD 易感性相关的 82 个 GWAS 基因座中的假定因果变异，并预测这些变异对肺细胞类型的调节影响。我们使用了一种具有统计精细映射、开放染色质分析和机器学习的综合方法来识别功能变异。我们使用高通量测序转座酶可及染色质分析 (ATAC-seq) 生成了染色质可及性数据，用于涉及 COPD 病理生物学的人类原代肺细胞类型。然后，我们评估了肺特异性开放染色质区域中 COPD 风险变异的富集，并针对对应于 82 个 COPD GWAS 基因座的 >6,500 种变异生成了细胞类型特异性调节预测。精细定位的变异与肺开放染色质区域的整合有助于确定具有潜在功能影响的推定调控元件中的 22 个变异。与 222 个 DNA 元素百科全书 (ENCODE) 细胞样本的功能预测进行比较，揭示了 COPD 变异体在肺上皮、内皮和免疫细胞中的细胞类型特异性调节作用。我们通过将 GWAS 基因座中的精细定位与细胞特异性调控分析相结合，确定了 COPD 风险的潜在因果变异，