美国斯坦福大学Paul A. Khavari团队近期取得重要工作进展，他们通过综合分析，发现了与神经精神疾病相关的功能调节变异。相关研究成果2023年10月19日在线发表于《自然—遗传学》杂志上。

据介绍，假定调节功能的非编码变异导致神经精神疾病的遗传性。在发育中的人类神经细胞中共研究了2221个非编码变体与10种神经精神障碍的风险相关性，包括自闭症谱系障碍、注意力缺陷多动障碍、双相情感障碍、边缘型人格障碍、重度抑郁症、广泛性焦虑症、恐慌症、创伤后应激障碍、强迫症和精神分裂症。

研究人员将表观基因组和转录组学数据与大规模平行报告基因分析相结合，在特定的神经细胞类型中鉴定出差异活性的单核苷酸变体（daSNV）。表达基因定位、网络分析和染色质环化鉴定了由这些daSNV调节的候选疾病相关靶基因。daSNV基因编辑与临床队列分析的后续整合表明，镁转运功能障碍可能会增加神经精神疾病的风险，并表明常见的遗传病理机制可能介导多种神经精神疾病共有的特定症状。

附：英文原文

Title: Integrative analyses highlight functional regulatory variants associated with neuropsychiatric diseases

Author: Guo, Margaret G., Reynolds, David L., Ang, Cheen E., Liu, Yingfei, Zhao, Yang, Donohue, Laura K. H., Siprashvili, Zurab, Yang, Xue, Yoo, Yongjin, Mondal, Smarajit, Hong, Audrey, Kain, Jessica, Meservey, Lindsey, Fabo, Tania, Elfaki, Ibtihal, Kellman, Laura N., Abell, Nathan S., Pershad, Yash, Bayat, Vafa, Etminani, Payam, Holodniy, Mark, Geschwind, Daniel H., Montgomery, Stephen B., Duncan, Laramie E., Urban, Alexander E., Altman, Russ B., Wernig, Marius, Khavari, Paul A.

Issue&Volume: 2023-10-19

Abstract: Noncoding variants of presumed regulatory function contribute to the heritability of neuropsychiatric disease. A total of 2,221 noncoding variants connected to risk for ten neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, borderline personality disorder, major depression, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder and schizophrenia, were studied in developing human neural cells. Integrating epigenomic and transcriptomic data with massively parallel reporter assays identified differentially-active single-nucleotide variants (daSNVs) in specific neural cell types. Expression-gene mapping, network analyses and chromatin looping nominated candidate disease-relevant target genes modulated by these daSNVs. Follow-up integration of daSNV gene editing with clinical cohort analyses suggested that magnesium transport dysfunction may increase neuropsychiatric disease risk and indicated that common genetic pathomechanisms may mediate specific symptoms that are shared across multiple neuropsychiatric diseases.

DOI: 10.1038/s41588-023-01533-5

Source: https://www.nature.com/articles/s41588-023-01533-5