DNA甲基化与精神分裂症相关中间表型之间的关联——基因集富集分析

Associations between DNA methylation and schizophrenia-related intermediate phenotypes - a gene set enrichment analysis.

作者信息

Hass Johanna, Walton Esther, Wright Carrie, Beyer Andreas, Scholz Markus, Turner Jessica, Liu Jingyu, Smolka Michael N, Roessner Veit, Sponheim Scott R, Gollub Randy L, Calhoun Vince D, Ehrlich Stefan

机构信息

Translational Developmental Neuroscience Section, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany.

Department of Neurosciences, Health Sciences Center, University of New Mexico, Albuquerque, NM, USA; The Mind Research Network, Albuquerque, NM USA.

出版信息

Prog Neuropsychopharmacol Biol Psychiatry. 2015 Jun 3;59:31-39. doi: 10.1016/j.pnpbp.2015.01.006. Epub 2015 Jan 15.

Abstract

Multiple genetic approaches have identified microRNAs as key effectors in psychiatric disorders as they post-transcriptionally regulate expression of thousands of target genes. However, their role in specific psychiatric diseases remains poorly understood. In addition, epigenetic mechanisms such as DNA methylation, which affect the expression of both microRNAs and coding genes, are critical for our understanding of molecular mechanisms in schizophrenia. Using clinical, imaging, genetic, and epigenetic data of 103 patients with schizophrenia and 111 healthy controls of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia, we conducted gene set enrichment analysis to identify markers for schizophrenia-associated intermediate phenotypes. Genes were ranked based on the correlation between DNA methylation patterns and each phenotype, and then searched for enrichment in 221 predicted microRNA target gene sets. We found the predicted hsa-miR-219a-5p target gene set to be significantly enriched for genes (EPHA4, PKNOX1, ESR1, among others) whose methylation status is correlated with hippocampal volume independent of disease status. Our results were strengthened by significant associations between hsa-miR-219a-5p target gene methylation patterns and hippocampus-related neuropsychological variables. IPA pathway analysis of the respective predicted hsa-miR-219a-5p target genes revealed associated network functions in behavior and developmental disorders. Altered methylation patterns of predicted hsa-miR-219a-5p target genes are associated with a structural aberration of the brain that has been proposed as a possible biomarker for schizophrenia. The (dys)regulation of microRNA target genes by epigenetic mechanisms may confer additional risk for developing psychiatric symptoms. Further study is needed to understand possible interactions between microRNAs and epigenetic changes and their impact on risk for brain-based disorders such as schizophrenia.

摘要

多种遗传学方法已确定微小RNA是精神疾病的关键效应因子,因为它们在转录后调节数千个靶基因的表达。然而,它们在特定精神疾病中的作用仍知之甚少。此外,诸如DNA甲基化等表观遗传机制会影响微小RNA和编码基因的表达,对于我们理解精神分裂症的分子机制至关重要。利用精神分裂症的精神临床影像联盟(MCIC)研究中103例精神分裂症患者和111名健康对照的临床、影像、遗传和表观遗传数据,我们进行了基因集富集分析,以确定精神分裂症相关中间表型的标志物。根据DNA甲基化模式与每种表型之间的相关性对基因进行排名,然后在221个预测的微小RNA靶基因集中搜索富集情况。我们发现预测的hsa-miR-219a-5p靶基因集在其甲基化状态与海马体积相关而与疾病状态无关的基因(如EPHA4、PKNOX1、ESR1等)中显著富集。hsa-miR-219a-5p靶基因甲基化模式与海马相关神经心理变量之间的显著关联加强了我们的研究结果。对各自预测的hsa-miR-219a-5p靶基因进行IPA通路分析,揭示了行为和发育障碍中的相关网络功能。预测的hsa-miR-219a-5p靶基因甲基化模式的改变与一种脑结构异常有关,这种异常已被提出作为精神分裂症的一种可能生物标志物。表观遗传机制对微小RNA靶基因的(失调)调节可能会增加出现精神症状的风险。需要进一步研究以了解微小RNA与表观遗传变化之间可能的相互作用及其对诸如精神分裂症等基于脑的疾病风险的影响。

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