脑基因共表达网络将补体信号与精神分裂症中的会聚性突触病变联系起来。

Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia.

机构信息

Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

出版信息

Nat Neurosci. 2021 Jun;24(6):799-809. doi: 10.1038/s41593-021-00847-z. Epub 2021 May 6.

DOI:10.1038/s41593-021-00847-z

PMID:33958802

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8178202/

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.

摘要

精神分裂症（SCZ）最显著的常见变异关联反映了补体成分 4A（C4A）表达增加。然而，目前尚不清楚 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 SCZ 的发病机制。在这里，我们整合了几个现有的大规模遗传和转录组数据集，以研究补体系统和 C4A 在人类大脑中的功能作用。出乎意料的是，我们没有发现已知的补体系统基因在 SCZ 中有显著的遗传富集。相反，使用 C4A 作为种子基因进行大脑共表达网络分析表明，当 C4A 表达增加时下调的基因，在 SCZ 风险方面表现出强烈而特异的遗传富集。这种收敛的基因组信号反映了突触过程，具有性别二态性，在前额皮质脑区最为明显，并受吸烟影响。总的来说，这些结果表明，是突触通路，而不是补体系统，为 SCZ 风险提供了驱动力。