近日，美国转化基因组研究所Nicholas E. Banovich及其团队，揭示了人类肺部的细胞特异性和疾病相关表达定量性状位点。相关论文于2024年3月28日在线发表于国际学术期刊《自然—遗传学》。

研究人员对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。研究人员使用伪批量方法绘制了38种细胞类型的表达定量性状位点（eQTL），观察到了共享的和细胞类型特异的调控效应。此外，研究人员还发现了疾病交互作用eQTL，并证明这类关联更有可能是细胞类型特异性的，并与肺纤维化中的细胞失调有关。

最后，研究人员将肺病风险变异与其在疾病相关细胞类型中的调控靶点联系起来。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，并表明特定环境的eQTL是肺部稳态和疾病的关键调节因子。

据悉，常见的基因变异会带来慢性肺部疾病（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的方式确定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生物学的机制至关重要。

附：英文原文

Title: Cell-type-specific and disease-associated expression quantitative trait loci in the human lung

Author: Natri, Heini M., Del Azodi, Christina B., Peter, Lance, Taylor, Chase J., Chugh, Sagrika, Kendle, Robert, Chung, Mei-i, Flaherty, David K., Matlock, Brittany K., Calvi, Carla L., Blackwell, Timothy S., Ware, Lorraine B., Bacchetta, Matthew, Walia, Rajat, Shaver, Ciara M., Kropski, Jonathan A., McCarthy, Davis J., Banovich, Nicholas E.

Issue&Volume: 2024-03-28

Abstract: 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.

DOI: 10.1038/s41588-024-01702-0

Source: https://www.nature.com/articles/s41588-024-01702-0