在TSNARE1和ADGRB1基因附近的一种功能性精神分裂症相关的遗传变异
Marah H Wahbeh1, Rachel J Boyd1, Christian Yovo1
1McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
HGG advances
|May 4, 2024
概括
这项研究研究了一种精神分裂症 (SCZ) 风险变异,rs4129585,接近ADGRB1. 研究人员发现这种变异是功能性的,影响神经细胞中的基因表达,并可能通过突触通路影响SCZ风险.
科学领域:
- 神经遗传学 神经遗传学
- 分子精神病学分子精神病学
背景情况:
- 全基因组关联研究 (GWAS) 已经确定了许多精神分裂症 (SCZ) 风险位,但常常缺乏变异性功能直接证据.
- 许多SCZ相关的变异与调节性表观遗传标记重叠,表明在基因调节中的作用.
- 位于TSNARE1和ADGRB1附近的特定变异rs4129585因其关联强度和监管潜力而被选中进行功能调查.
研究的目的:
- 为了确定SCZ风险变体rs4129585是否是功能性的.
- 为了研究rs4129585对相关细胞类型的基因表达的影响.
- 确定rs4129585调节的特定基因及其在SCZ病原发生中的作用.
主要方法:
- 在斑马鱼中进行记者基因测试,以评估变体序列的调节潜力.
- 产生同源的人类诱导多能干细胞 (hiPSC) 线,对 rs4129585.5 的风险或非风险等位基因均.
- 将hiPSCs分化为神经原生细胞,随后进行RNA测序,以确定异位基因特异的转录差异.
主要成果:
- 包含变异的序列在斑马鱼的神经元群体中表现出调节活性.
- RNA测序揭示了109个基因 (FDR <0.05) 和259个基因 (FDR <0.1) 的显著等位基因特异性转录差异.
- 差异表达的基因在突触功能至关重要的途径中得到丰富,包括突触蛋白,轴突指导和突触组装. 这种变异似乎调节ADGRB1,而不是TSNARE1.
结论:
- 这种SCZ风险变体rs4129585具有功能性,并通过调节ADGRB1来发挥作用,ADGRB1是一种参与突触发生的基因.
- 由rs4129585驱动的等位基因特异性基因表达变化涉及到SCZ风险中的突触通路.
- 这些发现提供了直接证据,表明常见变异在SCZ病原发生过程中通过影响神经元功能的调节机制发挥了作用.
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