The interaction of RELN–DNMT genes involving in neurotrophin signaling pathway contributes to schizophrenia susceptibility

IF 1.7 4区医学 Q3 DEVELOPMENTAL BIOLOGY International Journal of Developmental Neuroscience Pub Date : 2024-01-31 DOI:10.1002/jdn.10316

Junjiao Ping, Jing Wan, Jiali Luo, Baoguo Du, Xinxia Liu, Tingyun Jiang, Jie Zhang

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Abstract

Objective

Schizophrenia belongs to a severe mental illness with complicated clinical presentations, an ill-defined pathogenesis, and no known cause. Many genetic studies imply that polygenic interaction is important in the development of schizophrenia. The main mechanism of the RELN-BDNF-CREB-DNMT signaling pathway in neurodevelopment involves RELN, brain-derived neurotrophic factor (BDNF), transcription factor cyclic adenosine monophosphate response element binding protein (CREB), DNA methyltransferase 1 (DNMT1), as well as DNA methyltransferase 3B (DNMT3B). An early case–control research on 15 polymorphisms in the RELN, CREB, BDNF, DNMT1, and DNMT3B genes was done. A single gene variation has little effect on the pathogenesis of schizophrenia, but the combination of intergenic variation loci has a bigger impact because schizophrenia is a complex polygenic disorder. The objective of the current study sought to explore the impact of genetic interactions between RELN, BDNF, CREB, DNMT1, and DNMT3B on schizophrenia in order to further highlight the genetic factors influencing the risk of schizophrenia.

Methods

Taking the case–control study design, with the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) to be the evaluation norm, 134 individuals suffering from schizophrenia hospitalized in the Third People's Hospital of Zhongshan City within January 2018 to April 2020 (case group) were selected, and 64 healthy individuals (control group) from the same geographical area had been chosen as well. MassArray identified DNMT1 gene single nucleotide polymorphisms (rs2114724 and rs2228611) and DNMT3B gene SNPs (rs2424932, rs1569686, rs6119954, and rs2424908). Using the generalized multifactor dimensionality reduction (GMDR), the RELN-BDNF-CREB-DNMT pathway's gene interactions were examined for their impact on schizophrenia.

Results

GMDR analysis showed that the three-order interaction model RELN (rs2073559, rs2229864)–DNMT3B (rs2424908) was the optimal model (p = 0.001), with the consistency of cross-validation of 10/10 and the test accuracy of 0.8711.

Conclusion

The interaction between the RELN (rs2073559, rs2229864)–DNMT3B (rs2424908) may be related to schizophrenia, and large sample sizes should be verified in different population.

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涉及神经营养素信号通路的 RELN-DNMT 基因相互作用导致精神分裂症易感性。

目的：精神分裂症属于重性精神疾病，临床表现复杂，发病机制不明确，病因不明。许多遗传学研究表明，多基因相互作用在精神分裂症的发病中起着重要作用。RELN-BDNF-CREB-DNMT信号通路在神经发育中的主要机制涉及RELN、脑源性神经营养因子（BDNF）、转录因子环磷酸腺苷反应元件结合蛋白（CREB）、DNA甲基转移酶1（DNMT1）和DNA甲基转移酶3B（DNMT3B）。早期对 RELN、CREB、BDNF、DNMT1 和 DNMT3B 基因中的 15 个多态性进行了病例对照研究。单个基因变异对精神分裂症的发病机制影响不大，但基因间变异位点的组合影响更大，因为精神分裂症是一种复杂的多基因疾病。本研究旨在探讨RELN、BDNF、CREB、DNMT1和DNMT3B之间的遗传相互作用对精神分裂症的影响，以进一步揭示影响精神分裂症风险的遗传因素：方法：采用病例对照研究设计，以《精神疾病诊断与统计手册-第五版》（DSM-5）为评价标准，选择2018年1月至2020年4月在中山市第三人民医院住院治疗的134名精神分裂症患者（病例组），同时选择同一地区的64名健康人（对照组）。MassArray 鉴定了 DNMT1 基因单核苷酸多态性（rs2114724 和 rs2228611）和 DNMT3B 基因 SNPs（rs2424932、rs1569686、rs6119954 和 rs2424908）。利用广义多因素降维法（GMDR），研究了RELN-BDNF-CREB-DNMT通路基因相互作用对精神分裂症的影响：GMDR分析表明，RELN（rs2073559，rs2229864）-DNMT3B（rs2424908）三阶相互作用模型是最优模型（p=0.001），交叉验证一致性为10/10，测试准确率为0.8711：RELN（rs2073559、rs2229864）-DNMT3B（rs2424908）之间的相互作用可能与精神分裂症有关，应在不同人群中进行大样本验证。

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来源期刊

International Journal of Developmental Neuroscience 医学-发育生物学

CiteScore

3.30

自引率

5.60%

发文量

审稿时长

6-12 weeks

期刊介绍： International Journal of Developmental Neuroscience publishes original research articles and critical review papers on all fundamental and clinical aspects of nervous system development, renewal and regeneration, as well as on the effects of genetic and environmental perturbations of brain development and homeostasis leading to neurodevelopmental disorders and neurological conditions. Studies describing the involvement of stem cells in nervous system maintenance and disease (including brain tumours), stem cell-based approaches for the investigation of neurodegenerative diseases, roles of neuroinflammation in development and disease, and neuroevolution are also encouraged. Investigations using molecular, cellular, physiological, genetic and epigenetic approaches in model systems ranging from simple invertebrates to human iPSC-based 2D and 3D models are encouraged, as are studies using experimental models that provide behavioural or evolutionary insights. The journal also publishes Special Issues dealing with topics at the cutting edge of research edited by Guest Editors appointed by the Editor in Chief. A major aim of the journal is to facilitate the transfer of fundamental studies of nervous system development, maintenance, and disease to clinical applications. The journal thus intends to disseminate valuable information for both biologists and physicians. International Journal of Developmental Neuroscience is owned and supported by The International Society for Developmental Neuroscience (ISDN), an organization of scientists interested in advancing developmental neuroscience research in the broadest sense.