美国加州大学洛杉矶分校Michael J. Gandal研究团队发现，补体信号与精神分裂症的突触病理存在关联。该研究于2021年5月6日在线发表于国际一流学术期刊《自然—神经科学》。
研究人员整合了几个现有的大规模遗传和转录组数据集，用于研究补体系统和补体成分4A（C4A）在人脑中的功能作用。出乎意料的是，研究人员发现精神分裂症（SCZ）的已知补体系统基因之间没有显著的遗传富集。相反，使用C4A作为种子基因的大脑共表达网络分析显示，当C4A表达增加时被下调的基因表现出针对SCZ风险的明显遗传富集。这种收敛的基因组信号反映了突触过程，这是性二态性的，在额叶皮层大脑区域最突出，并且通过吸烟而加剧。总体而言，这些结果表明，突触途径而不是补体系统是赋予了SCZ风险的驱动力。
据了解，SCZ的最显著的常见变异关联反映了C4A的表达增加。然而，尚不清楚C4A如何与其他SCZ风险基因相互作用，或者补体系统是否更广泛地参与了SCZ发病机制。
附：英文原文
Title: Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia
Author: Minsoo Kim, Jillian R. Haney, Pan Zhang, Leanna M. Hernandez, Lee-kai Wang, Laura Perez-Cano, Loes M. Olde Loohuis, Luis de la Torre-Ubieta, Michael J. Gandal
Issue&Volume: 2021-05-06
Abstract: The most significant common variant association for schizophrenia (SCZ) reflects increased expression of the complement component 4A (C4A). Yet, it remains unclear how C4A interacts with other SCZ risk genes or whether the complement system more broadly is implicated in SCZ pathogenesis. Here, we integrate several existing, large-scale genetic and transcriptomic datasets to interrogate the functional role of the complement system and C4A in the human brain. Unexpectedly, we find no significant genetic enrichment among known complement system genes for SCZ. Conversely, brain co-expression network analyses using C4A as a seed gene reveal that genes downregulated when C4A expression increases exhibit strong and specific genetic enrichment for SCZ risk. This convergent genomic signal reflects synaptic processes, is sexually dimorphic and most prominent in frontal cortical brain regions, and is accentuated by smoking. Overall, these results indicate that synaptic pathways—rather than the complement system—are the driving force conferring SCZ risk.
DOI: 10.1038/s41593-021-00847-z
Source: https://www.nature.com/articles/s41593-021-00847-z
Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex
本期文章：《自然—神经科学》：Online/在线发表
