Expression quantitative trait loci (eQTL) represent genetic variants that regulate gene expression levels. eQTL analysis has become a crucial method for identifying the functional roles of disease-associated genetic variants in the post-genome-wide association study (GWAS) era, yielding numerous significant discoveries. Traditional eQTL analysis relies on whole-genome sequencing combined with bulk RNA-seq, which obscures gene expression differences between cells and thus fails to identify cell type- or state-dependent eQTL. This limitation makes it challenging to elucidate the roles of disease-associated genetic variants under specific conditions. In recent years, with the development and widespread application of single-cell RNA sequencing (scRNA-seq) technology, scRNA-seq-based eQTL (sc-eQTL) research has emerged as a focal point. The advantage of this approach lies in its ability to leverage the resolution and granularity of single-cell sequencing to uncover eQTL that are dependent on cell type, cell state, and cellular dynamics. This significantly enhances our ability to analyze genetic variants associated with gene expression. Consequently, it holds substantial significance for advancing our understanding of the formation of complex organs and the mechanisms underlying disease onset, progression, intervention, and treatment. This review comprehensively examines the recent advancements in sc-eQTL studies, focusing on their development, experimental design strategies, modeling approaches, and current challenges. The aim is to offer researchers novel perspectives for identifying disease-associated loci and elucidating gene regulatory mechanisms.
表达数量性状位点(expression quantitative trait loci，eQTL)表示控制基因表达量的遗传变异位点。eQTL分析是后全基因组关联研究时代鉴定疾病相关遗传位点功能的重要方法，且取得了诸多重要发现。传统的eQTL分析基于全基因组测序结合整体RNA测序技术，细胞间差异的基因表达水平会被掩盖，从而无法鉴定细胞类型或状态依赖的eQTL，因此也难以解析特定环境下疾病相关遗传变异位点。近年来，随着单细胞转录组测序技术的发展和应用普及，基于单细胞转录组测序的eQTL (single-cell RNA sequencing-based eQTL，sc-eQTL)研究技术逐渐成为热点，其优势在于可以充分利用单细胞测序的分辨率和颗粒度挖掘细胞类型、细胞状态以及细胞动态依赖的表达变异位点，显著提升解析基因表达关联的遗传变异位点的能力，对人们探究复杂器官的形成以及疾病的发生、发展、干预和治疗具有重要意义。本文主要从sc-eQTL研究的发展、设计方案、建模策略以及面临的挑战等诸多方面综述近年来的研究进展，以期为科研工作者挖掘致病位点，解析基因调控提供全新的视角。.
Keywords: cell-type specificity; expression quantitative trait loci; genetic regulatory element; genome-wide association study; single cell RNA-seq.