小柯机器人

德国马克斯·普朗克精神病学研究所Michael J. Ziller团队，报道了精神分裂症(SCZ)相关非编码基因变异的大规模平行功能解剖。该项研究成果发表在2023年10月17日出版的《细胞》上。

他们实现了一个大规模并行变异注释管道(MVAP)，在疾病相关的神经细胞类型中执行SCZ变异到功能的大规模映射。该方法确定了620种功能变异(1.7%)，这些变异在高度发育的背景下和神经元活动依赖的方式下运作。表观基因组和CRISPRi筛选数据的多模式整合使他们能够将这些功能变异与靶基因、生物过程以及最终的神经元生理改变联系起来。

这些结果为绘制功能性单核苷酸多态性(SNP)-基因-内表型关系提供了多阶段优先排序策略，并SCZ相关遗传变异调控的环境依赖分子过程提供了生物学见解。

据悉，SCZ是一种高度遗传性的精神障碍，其数千种相关的遗传变异主要位于基因组的非编码空间。将这些关联转化为关于潜在病理机制的见解一直具有挑战性，因为因果变异、它们的作用机制和它们的靶基因在很大程度上仍然未知。

附：英文原文

Title: Massively parallel functional dissection of schizophrenia-associated noncoding genetic variants

Author: Christine K. Rummel, Miriam Gagliardi, Ruhel Ahmad, Alexander Herholt, Laura Jimenez-Barron, Vanessa Murek, Liesa Weigert, Anna Hausruckinger, Susanne Maidl, Barbara Hauger, Florian J. Raabe, Christina Fürle, Lucia Trastulla, Gustavo Turecki, Matthias Eder, Moritz J. Rossner, Michael J. Ziller

Issue&Volume: 2023-10-17

Abstract: Schizophrenia (SCZ) is a highly heritable mental disorder with thousands of associatedgenetic variants located mostly in the noncoding space of the genome. Translatingthese associations into insights regarding the underlying pathomechanisms has beenchallenging because the causal variants, their mechanisms of action, and their targetgenes remain largely unknown. We implemented a massively parallel variant annotationpipeline (MVAP) to perform SCZ variant-to-function mapping at scale in disease-relevantneural cell types. This approach identified 620 functional variants (1.7%) that operatein a highly developmental context and neuronal-activity-dependent manner. Multimodalintegration of epigenomic and CRISPRi screening data enabled us to link these functionalvariants to target genes, biological processes, and ultimately alterations of neuronalphysiology. These results provide a multistage prioritization strategy to map functionalsingle-nucleotide polymorphism (SNP)-to-gene-to-endophenotype relations and offerbiological insights into the context-dependent molecular processes modulated by SCZ-associatedgenetic variation.

DOI: 10.1016/j.cell.2023.09.015

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01036-X