Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia.
Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia.
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DOI：
10.1038/s41593-021-00847-z
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发表时间：
2021-06
影响因子：
25
通讯作者：
Gandal MJ
中科院分区：
文献类型：
--
作者：
Kim M;Haney JR;Zhang P;Hernandez LM;Wang LK;Perez-Cano L;Loohuis LMO;de la Torre-Ubieta L;Gandal MJ
精神分裂症（SCZ）最重要的常见变异关联反映了补体成分4A（C4A）表达的增加。然而，目前仍不清楚C4A如何与其他精神分裂症风险基因相互作用，以及补体系统是否在精神分裂症的发病机制中具有更广泛的影响。在此，我们整合了几个现有的大规模遗传和转录组数据集，以探究补体系统和C4A在人脑中的功能作用。令人惊讶的是，我们发现已知的补体系统基因在精神分裂症方面没有显著的遗传富集。相反，以C4A作为种子基因的脑共表达网络分析显示，当C4A表达增加时下调的基因在精神分裂症风险方面表现出强烈且特异的遗传富集。这种汇聚的基因组信号反映了神经元和突触过程，具有性别二态性，并且在额叶皮质脑区最为显著。总体而言，这些结果表明，突触通路——而非补体系统——是导致精神分裂症风险的驱动力。
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 and whether the complement system is more broadly 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. Surprisingly, 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 revealed that genes down-regulated when C4A expression increased exhibit strong and specific genetic enrichment for SCZ risk. This convergent genomic signal reflected neuronal, synaptic processes and was sexually dimorphic and most prominent in frontal cortical brain regions. Overall, these results indicate that synaptic pathways—rather than the complement system—are the driving force conferring SCZ risk.
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影响因子：
11
作者：
International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Studies (OCGAS)
通讯作者：
International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Studies (OCGAS)
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
30.8
作者：
Finucane HK;Reshef YA;Anttila V;Slowikowski K;Gusev A;Byrnes A;Gazal S;Loh PR;Lareau C;Shoresh N;Genovese G;Saunders A;Macosko E;Pollack S;Brainstorm Consortium;Perry JRB;Buenrostro JD;Bernstein BE;Raychaudhuri S;McCarroll S;Neale BM;Price AL
通讯作者：
Price AL
自闭症谱系障碍（ASD）、精神分裂症和双相情感障碍中全转录组异构体水平失调
影响因子：
56.9
作者：
Gandal, Michael J.;Zhang, Pan;Geschwind, Daniel H.
通讯作者：
Geschwind, Daniel H.
影响因子：
16.2
作者：
Collado-Torres, Leonardo;Burke, Emily E.;Narurkar, Rujuta
通讯作者：
Narurkar, Rujuta