功能性调节变异涉及痴呆症中不同的转录网络
Yonatan A Cooper1,2,3, Noam Teyssier4, Nina M Dräger4
1Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
概括
识别阿尔茨海默病 (AD) 和渐进性超核性 (PSP) 的功能变异是关键. 这项研究发现320种功能调节变体 (frVars) 影响基因网络,进步了我们对神经退行性疾病遗传学的理解.
科学领域:
- 遗传学
- 神经科学
- 基因组学
背景情况:
- 预测非编码基因变异的功能影响仍然是遗传学的重大挑战.
- 全基因组关联研究 (GWAS) 已经确定了许多与阿尔茨海默病 (AD) 和渐进性超核性 (PSP) 等复杂疾病相关的遗传位置,但很难确定因果变异.
研究的目的:
- 系统查和识别与阿尔茨海默病 (AD) 和渐进性上核性 (PSP) 相关的功能调节变异.
- 验证已识别的风险位置并阐明这些神经退行性疾病中非编码遗传风险的分子机制.
主要方法:
- 使用大规模并行报告测试 (MPRA) 选5706个GWAS识别的变体进行调节功能.
- 使用CRISPR干扰或切割来验证已识别的风险位置.
- 以细胞类型特定的方式分析了转录因子结合部位和增强剂活性的功能变异.
主要成果:
- 在包括17q21.31区域在内的27个位点中确定了320个功能调节变异 (frVars).
- 验证了多个AD风险位点 (例如C4A,APOC1) 和PSP (例如PLEKHM1,KANSL1).
- 发现功能变体汇聚在细胞类型特定的增强剂上,涉及神经元SP1驱动的调节网络在PSP的发病过程中.
结论:
- 在AD和PSP中,非编码的遗传风险主要是由通过特定的转录程序作用的常见变异驱动的.
- 这些发现突显了功能基因组学在解剖神经退行性疾病的遗传结构方面的重要性.
- 揭示了神经元SP1驱动的调节网络,有助于PSP的发病,提供了潜在的治疗点.
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