人类大脑蛋白质组的遗传调节揭示了与精神疾病有关的蛋白质
Jie Luo1, Ling Li2, Mingming Niu3
1State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, 310021, China.
Molecular psychiatry
|May 9, 2024
概括
这项研究绘制了人类大脑蛋白质表达的地图,确定了与精神疾病的遗传联系. 蛋白质组学揭示了非同义变体调节蛋白质水平,为精神分裂症病原体提供了新的见解.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 遗传学 是一个
- 精神病学是一个精神病学.
背景情况:
- 精神疾病具有高度的遗传性和多基因性,涉及数百个风险基因.
- 全基因组关联研究 (GWAS) 已经确定了与精神疾病相关的众多遗传位置,但它们的功能作用仍然不清楚.
研究的目的:
- 为了研究人类大脑蛋白质表达的遗传调节.
- 为了确定与精神分裂症有因果关系的蛋白质和基因.
- 探索蛋白质定量特征位点 (pQTLs) 对精神疾病病因学的贡献.
主要方法:
- 在268名受试者中生成了深层人类大脑蛋白质组学数据,使用11-plex双重质量标签和2DLC-MS/MS.
- 进行全基因组关联分析以确定cis-acting蛋白质定量特征位点 (cis-pQTLs).
- 利用调解分析,门德尔的随机化和多omics集成与网络分析.
主要成果:
- 鉴定了788个与883个蛋白质相关的cis-pQTLs,全基因组错误发现率<5%.
- 发现的蛋白质表达主要由非同义变体调节,与转录水平不同.
- 在基因表达和蛋白质丰富之间发现了76个共享的调节信号.
- 通过孟德尔随机化识别了4种蛋白质和19种因果关系与精神分裂症相关的基因.
结论:
- 整个蛋白质组的链接分析提供了对精神疾病发病的机制性见解.
- 通过非同义变体调节蛋白质表达是精神病遗传学的关键因素.
- 这项研究为优先考虑精神疾病候选基因提供了基础.
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