美国圣路易斯华盛顿大学医学院Carlos Cruchaga小组绘制出大脑、脑脊液和血浆蛋白质组的基因组图谱。相关论文于2021年7月8日在线发表于国际学术期刊《自然—神经科学》杂志上。

通过分析患有和未患有阿尔茨海默病参与者的数千种蛋白质，研究人员在与神经系统疾病相关的三个组织（大脑、脑脊液和血浆）中生成了蛋白质水平的基因组图谱。研究人员分别鉴定了脑脊液、血浆和大脑的274、127和32个蛋白质数量性状基因座 (pQTL)。cis-pQTL更有可能是组织共享的，但trans-pQTL往往是组织特异性的。48.0%到76.6%的 pQTL不与表达、剪接、DNA甲基化或组蛋白乙酰化QTL共定位。

使用孟德尔随机化，研究人员挑选了与神经系统疾病有关的蛋白质，包括阿尔茨海默病、帕金森病和中风。这项多组织研究将有助于将来自全基因组关联研究的信号映射到功能基因上，进而发现通路并确定神经疾病的药物靶点。

据介绍，了解蛋白质水平的组织特异性遗传控制对于揭示转录后基因调控的机制至关重要。

附：英文原文

Title: Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders

Author: Chengran Yang, Fabiana H. G. Farias, Laura Ibanez, Adam Suhy, Brooke Sadler, Maria Victoria Fernandez, Fengxian Wang, Joseph L. Bradley, Brett Eiffert, Jorge A. Bahena, John P. Budde, Zeran Li, Umber Dube, Yun Ju Sung, Kathie A. Mihindukulasuriya, John C. Morris, Anne M. Fagan, Richard J. Perrin, Bruno A. Benitez, Herve Rhinn, Oscar Harari, Carlos Cruchaga

Issue&Volume: 2021-07-08

Abstract: Understanding the tissue-specific genetic controls of protein levels is essential to uncover mechanisms of post-transcriptional gene regulation. In this study, we generated a genomic atlas of protein levels in three tissues relevant to neurological disorders (brain, cerebrospinal fluid and plasma) by profiling thousands of proteins from participants with and without Alzheimer’s disease. We identified 274, 127 and 32 protein quantitative trait loci (pQTLs) for cerebrospinal fluid, plasma and brain, respectively. cis-pQTLs were more likely to be tissue shared, but trans-pQTLs tended to be tissue specific. Between 48.0% and 76.6% of pQTLs did not co-localize with expression, splicing, DNA methylation or histone acetylation QTLs. Using Mendelian randomization, we nominated proteins implicated in neurological diseases, including Alzheimer’s disease, Parkinson’s disease and stroke. This first multi-tissue study will be instrumental to map signals from genome-wide association studies onto functional genes, to discover pathways and to identify drug targets for neurological diseases.

DOI: 10.1038/s41593-021-00886-6

Source: https://www.nature.com/articles/s41593-021-00886-6