近日，美国北卡罗来纳大学Hyejung Won及其研究团队发现，大规模平行报告实验研究八种精神疾病的共同遗传变异。2025年1月22日，《细胞》杂志在线发表了这项成果。

研究人员进行了大规模平行报告实验，以解码具有多效性和疾病特异性效应的变异的调控逻辑。与疾病特异性变异不同，多效性变异表现出跨多个神经细胞谱系类型的染色质可及性，并且改变了转录因子的结合位点，这些转录因子在蛋白质-蛋白质相互作用网络中具有更高的连接性。

研究人员使用功能基因组学方法和CRISPR干扰技术，将多效性和疾病特异性变异映射到潜在靶基因。对多效性基因和疾病特异性基因的体内CRISPR干扰表明，多效性可能涉及广泛表达于神经元细胞类型的基因调控，并具有更高的网络连接性。

据了解，一项跨越八种精神疾病的元基因组广泛关联研究揭示了主要精神疾病的多效性遗传结构。然而，相关变异的多效应机制仍待探索。

附：英文原文

Title: Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders

Author: Sool Lee, Jessica C. McAfee, Jiseok Lee, Alejandro Gomez, Austin T. Ledford, Declan Clarke, Hyunggyu Min, Mark B. Gerstein, Alan P. Boyle, Patrick F. Sullivan, Adriana S. Beltran, Hyejung Won

Issue&Volume: 2025-01-22

Abstract: A meta-genome-wide association study across eight psychiatric disorders has highlighted the genetic architecture of pleiotropy in major psychiatric disorders. However, mechanisms underlying pleiotropic effects of the associated variants remain to be explored. We conducted a massively parallel reporter assay to decode the regulatory logic of variants with pleiotropic and disorder-specific effects. Pleiotropic variants differ from disorder-specific variants by exhibiting chromatin accessibility that extends across diverse cell types in the neuronal lineage and by altering motifs for transcription factors with higher connectivity in protein-protein interaction networks. We mapped pleiotropic and disorder-specific variants to putative target genes using functional genomics approaches and CRISPR perturbation. In vivo CRISPR perturbation of a pleiotropic and a disorder-specific gene suggests that pleiotropy may involve the regulation of genes expressed broadly across neuronal cell types and with higher network connectivity.

DOI: 10.1016/j.cell.2024.12.022

Source: https://www.cell.com/cell/abstract/S0092-8674(24)01435-1