Mental Health Center and Psychiatric Laboratory, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
Nanhu Brain-computer Interface Institute, Hangzhou 311100, China.
Psychol Med. 2024 Jul;54(9):2054-2062. doi: 10.1017/S003329172400014X. Epub 2024 Mar 6.
Over the past several decades, more research focuses have been made on the inflammation/immune hypothesis of schizophrenia. Building upon synaptic plasticity hypothesis, inflammation may contribute the underlying pathophysiology of schizophrenia. Yet, pinpointing the specific inflammatory agents responsible for schizophrenia remains a complex challenge, mainly due to medication and metabolic status. Multiple lines of evidence point to a wide-spread genetic association across genome underlying the phenotypic variations of schizophrenia.
We collected the latest genome-wide association analysis (GWAS) summary data of schizophrenia, cytokines, and longitudinal change of brain. We utilized the omnigenic model which takes into account all genomic SNPs included in the GWAS of trait, instead of traditional Mendelian randomization (MR) methods. We conducted two round MR to investigate the inflammatory triggers of schizophrenia and the resulting longitudinal changes in the brain.
We identified seven inflammation markers linked to schizophrenia onset, which all passed the Bonferroni correction for multiple comparisons (bNGF, GROA(CXCL1), IL-8, M-CSF, MCP-3 (CCL7), TNF-, CRP). Moreover, CRP were found to significantly influence the linear rate of brain morphology changes, predominantly in the white matter of the cerebrum and cerebellum.
With an omnigenic approach, our study sheds light on the immune pathology of schizophrenia. Although these findings need confirmation from future studies employing different methodologies, our work provides substantial evidence that pervasive, low-level neuroinflammation may play a pivotal role in schizophrenia, potentially leading to notable longitudinal changes in brain morphology.
在过去几十年中，越来越多的研究关注精神分裂症的炎症/免疫假说。在突触可塑性假说的基础上，炎症可能是精神分裂症潜在病理生理学的原因。然而，确定导致精神分裂症的特定炎症因子仍然是一个复杂的挑战，主要是由于药物和代谢状态的影响。有多项证据表明，广泛的遗传关联存在于精神分裂症表型变异的基因组中。
我们收集了最新的精神分裂症全基因组关联分析（GWAS）总结数据、细胞因子和大脑的纵向变化。我们利用全基因组关联分析中的所有基因组 SNP 的全基因组模型（omnigenic model），而不是传统的孟德尔随机化（MR）方法。我们进行了两轮 MR 分析，以研究精神分裂症的炎症触发因素及其对大脑纵向变化的影响。
我们确定了与精神分裂症发病相关的七个炎症标志物，这些标志物都通过了多重比较的 Bonferroni 校正（bNGF、GROA（CXCL1）、IL-8、M-CSF、MCP-3（CCL7）、TNF-、CRP）。此外，CRP 被发现显著影响大脑形态变化的线性速率，主要影响大脑和小脑的白质。
通过全基因组模型方法，我们的研究揭示了精神分裂症的免疫病理学。尽管这些发现需要未来采用不同方法学的研究进行证实，但我们的工作提供了充分的证据表明，普遍存在的低度神经炎症可能在精神分裂症中发挥关键作用，可能导致大脑形态的显著纵向变化。
