Common genetic variants confer substantial risk for chronic lung diseases, including pulmonary fibrosis. Defining the genetic control of gene expression in a cell-type-specific and context-dependent manner is critical for understanding the mechanisms through which genetic variation influences complex traits and disease pathobiology. To this end, we performed single-cell RNA sequencing of lung tissue from 66 individuals with pulmonary fibrosis and 48 unaffected donors. Using a pseudobulk approach, we mapped expression quantitative trait loci (eQTLs) across 38 cell types, observing both shared and cell-type-specific regulatory effects. Furthermore, we identified disease interaction eQTLs and demonstrated that this class of associations is more likely to be cell-type-specific and linked to cellular dysregulation in pulmonary fibrosis. Finally, we connected lung disease risk variants to their regulatory targets in disease-relevant cell types. These results indicate that cellular context determines the impact of genetic variation on gene expression and implicates context-specific eQTLs as key regulators of lung homeostasis and disease.

常见的基因变异会带来罹患慢性肺部疾病（包括肺纤维化）的巨大风险。以细胞类型特异性和环境依赖性方式定义基因表达的遗传控制对于理解遗传变异影响复杂性状和疾病病理学的机制至关重要。为此，我们对 66 名肺纤维化患者和 48 名未受影响的供体的肺组织进行了单细胞 RNA 测序。使用伪批量方法，我们绘制了 38 种细胞类型的表达数量性状位点 (eQTL)，观察了共享的和细胞类型特异性的调节效应。此外，我们还确定了疾病相互作用的 eQTL，并证明此类关联更有可能是细胞类型特异性的，并且与肺纤维化中的细胞失调有关。最后，我们将肺部疾病风险变异与其疾病相关细胞类型的调节目标联系起来。这些结果表明，细胞环境决定了遗传变异对基因表达的影响，并暗示环境特异性 eQTL 作为肺稳态和疾病的关键调节因子。