Cell type-specific and disease-associated eQTL in the human lung.
Cell type-specific and disease-associated eQTL in the human lung.
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人肺中细胞类型特异性和疾病相关的 eQTL。
DOI：
10.1101/2023.03.17.533161
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Shaver,
中科院分区：
文献类型：
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作者：
Natri,HeiniM;DelAzodi,ChristinaB;Peter,Lance;Taylor,ChaseJ;Chugh,Sagrika;Kendle,Robert;Chung,Mei-I;Flaherty,DavidK;Matlock,BrittanyK;Calvi,CarlaL;Blackwell,TimothyS;Ware,LorraineB;Bacchetta,Matthew;Walia,Rajat;Shaver,
常见的基因变异会带来患慢性肺部疾病的巨大风险，包括肺纤维化（PF）。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 67 名 PF 和 49 名未受影响供体的肺组织进行了单细胞 RNA 测序。采用伪批量方法，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 eQTL，并证明此类关联更有可能是细胞类型特异性的，并且与 PF 中的细胞失调有关。最后，我们将 PF 风险变异与其疾病相关细胞类型中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。
Common genetic variants confer substantial risk for chronic lung diseases, including pulmonary fibrosis (PF). 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 67 PF and 49 unaffected donors. Employing a pseudo-bulk approach, we mapped expression quantitative trait loci (eQTL) across 38 cell types, observing both shared and cell type-specific regulatory effects. Further, we identified disease-interaction eQTL and demonstrated that this class of associations is more likely to be cell-type specific and linked to cellular dysregulation in PF. Finally, we connected PF 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 eQTL as key regulators of lung homeostasis and disease.