细胞类型特异性eQTL是复杂性状遗传结构的基础

细胞类型特异性eQTL是复杂性状遗传结构的基础

作者： 小柯机器人 发布时间：2026/8/27 22:00:36

本期文章：《自然》：Online/在线发表

2026年8月26日，美国芝加哥大学Andy Dahl等科学家在《自然》发表研究，揭示了细胞类型特异性eQTL在复杂性状遗传架构中的核心作用。

遗传对复杂性状的影响主要通过调控基因表达来实现；然而，这一过程尚不完全清楚。对基因表达遗传效应（表达数量性状位点，eQTL）的研究有助于理解遗传变异与复杂性状之间的基因调控层。然而，以往的研究未能有效捕获细胞类型特异性eQTL，而这类eQTL可能对复杂性状至关重要。在此，研究人员通过将方差组分模型应用于人群规模的单细胞RNA测序（RNA-seq）数据，无偏地鉴定了细胞类型特异性eQTL。利用OneK1K队列的外周血单个核细胞数据，他们证明了细胞类型特异性eQTL富集了复杂性状的遗传力，而细胞类型共享eQTL则未观察到这一现象。他们还发现，eQTL的特异性与基因具有更强的选择约束、增强子复杂性和基因网络连接性相关，这三种特征在复杂性状中相较于已知eQTL更为富集。在转录组范围内，反式eQTL大部分是细胞类型特异性的（60%为特异性），而顺式eQTL则大部分是共享的（30%为特异性）。研究人员使用第二个单细胞RNA-seq数据集重复了他们的发现，并证明细胞类型共享和细胞类型特异性eQTL在不同祖先中是一致的。他们的结果确立了eQTL细胞类型特异性作为基因调控的一个关键特征，并部分解释了为什么已知eQTL在复杂性状的基因调控效应中有所缺失。

附：英文原文

Title: Cell-type-specific eQTLs underlie the genetic architecture of complex traits

Author: Chen, Minhui, Wang, Xinpei, Krockenberger, Lena, Tyebally, Rika, Berg, Jeremy J., Pott, Sebastian, Flint, Jonathan, Powell, Joseph E., Balliu, Brunilda, Liu, Xuanyao, Dahl, Andy

Issue&Volume: 2026-08-26

Abstract: Genetic effects on complex traits primarily act by regulating gene expression; however, this process is not well understood. Studies of genetic effects on gene expression (expression quantitative trait loci (eQTLs)) can inform as to the gene regulatory layer between genetic variants and complex traits. However, previous studies have not effectively captured cell-type-specific eQTLs, which are likely to be important for complex traits. Here we unbiasedly characterized cell-type-specific eQTLs by applying a variance component model to population-scale single-cell RNA-sequencing (RNA-seq) data. Using peripheral blood mononuclear cells from the OneK1K cohort, we demonstrated that cell-type-specific eQTLs enrich for complex trait heritability, which we did not observe for cell-type-shared eQTLs. We also found that eQTL specificity is associated with genes that have greater selective constraint, enhancer complexity and gene network connectivity, three features enriched in complex traits relative to known eQTLs. Transcriptome-wide, trans eQTLs were mostly cell-type-specific (60% specific) whereas cis eQTLs were mostly shared (30% specific). We used a second single-cell RNA-seq dataset to replicate our findings and demonstrate that cell-type-shared and cell-type-specific eQTLs are consistent across ancestries. Our results establish eQTL cell-type specificity as a key feature of gene regulation and partly explain why known eQTLs are depleted in gene regulatory effects on complex traits.

DOI: 10.1038/s41586-026-10577-6

Source: https://www.nature.com/articles/s41586-026-10577-6

主题：复杂性状|细胞类型特异性eQTL|研究