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大规模并行报告员测试在QT间隔GWAS loci中识别功能增强剂变体

Dongwon Lee^1,2,3, Lavanya Gunamalai⁴, Jeerthi Kannan^1,3

¹Department of Pediatrics, Division of Nephrology, Boston Children's Hospital, Boston, MA, USA.

bioRxiv : the preprint server for biology

|March 31, 2025

概括

这项研究通过分析转录增强剂中的遗传变异来确定影响心电 QT 间隔 (QTi) 变化的新型心脏基因. 它揭示了特定的DNA序列和转录因子结合如何改变基因表达,影响心脏功能.

科学领域:

遗传学是一个遗传学.
心脏病学心脏病学
分子生物学分子生物学

背景情况:

全基因组关联研究 (GWAS) 已经将30多个遗传位置与心电 QT 间隔 (QTi) 的变化联系起来.
这些位点内的非编码变体被涉及,但它们的功能机制,特别是涉及转录增强剂,仍然在很大程度上未被探索.

研究的目的:

识别影响QTi变化的转录增强剂及其变体.
确定特定转录因子 (TF) 的作用及其结合在调节与QTi相关的心脏基因表达中的作用.

主要方法:

大规模并行记者测试 (MPRA) 用于选1018个QTi相关的GWAS变体,在HL-1细胞中重叠候选心脏增强剂.
使用表达量性特征位点 (eQTL) 映射和促进体-增强体接触预测来识别目标基因.

主要成果:

确定了445种含有GWAS变体的增强剂,其中79种在21个位点之间显示出显著的基活性差异.
在49种增强剂变体中预测了关键心脏TFs (例如NKX2.5,SRF,TBX5) 的差异结合.
通过16个位置的36个增强器变体,确定了14个候选向基因,10个影响QTi变异的新型基因.

结论:

这项研究提供了14个影响QTi变化的心脏基因的有力证据,超出了以前已知的关联.
这些发现强调了转录增强剂和TF结合在QTi变异的遗传敏感性中的关键作用.

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