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      Potential clinical value of circular RNAs as peripheral biomarkers for the diagnosis and treatment of major depressive disorder

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          Abstract

          Background

          circular RNAs (circRNAs) are expressed abundantly in the brain and are implicated in the pathophysiology of neuropsychiatric disease. However, the potential clinical value of circRNAs in major depressive disorder (MDD) remains unclear.

          Methods

          RNA sequencing was conducted in whole-blood samples in a discovery set (7 highly homogeneous MDD patients and 7 matched healthy controls [HCs]). The differential expression of circRNAs was verified in an independent validation set. The interventional study was conducted to assess the potential effect of the antidepressive treatment on the circRNA expression.

          Findings

          in the validation set, compared with 52 HCs, significantly decreased circFKBP8 levels (Diff: -0.24; [95% CI -0.39 ~ -0.09]) and significantly elevated circMBNL1 levels (Diff: 0.37; [95% CI 0.09 ~ 0.64]) were observed in 53 MDD patients. The expression of circMBNL1 was negatively correlated with 24-item Hamilton Depression Scale (HAMD-24) scores in 53 MDD patients. A mediation model indicated that circMBNL1 affected HAMD-24 scores through a mediator, serum brain-derived neurotrophic factor. In 53 MDD patients, the amplitude of low-frequency fluctuations in the right orbital part middle frontal gyrus was positively correlated with circFKBP8 and circMBNL1 expression. Furthermore, the interventional study of 53 MDD patients demonstrated that antidepressive treatment partly increased circFKBP8 expression and the change in expression of circFKBP8 was predictive of further reduced HAMD-24 scores.

          Interpretation

          whole-blood circFKBP8 and circMBNL1 may be potential biomarkers for the diagnosis of MDD, respectively, and circFKBP8 may show great potential for the antidepressive treatment.

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          Most cited references87

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          Circular RNAs are a large class of animal RNAs with regulatory potency.

          Sebastian Memczak, Marvin Jens, Antigoni Elefsinioti … (2013)
          Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.
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            The biogenesis, biology and characterization of circular RNAs

            Lasse S. Kristensen, Maria Andersen, Lotte V. W. Stagsted … (2019)
            Circular RNAs (circRNAs) are covalently closed, endogenous biomolecules in eukaryotes with tissue-specific and cell-specific expression patterns, whose biogenesis is regulated by specific cis-acting elements and trans-acting factors. Some circRNAs are abundant and evolutionarily conserved, and many circRNAs exert important biological functions by acting as microRNA or protein inhibitors ('sponges'), by regulating protein function or by being translated themselves. Furthermore, circRNAs have been implicated in diseases such as diabetes mellitus, neurological disorders, cardiovascular diseases and cancer. Although the circular nature of these transcripts makes their detection, quantification and functional characterization challenging, recent advances in high-throughput RNA sequencing and circRNA-specific computational tools have driven the development of state-of-the-art approaches for their identification, and novel approaches to functional characterization are emerging.
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              Depression

              Gin Malhi, J John Mann (2018)
              Major depression is a common illness that severely limits psychosocial functioning and diminishes quality of life. In 2008, WHO ranked major depression as the third cause of burden of disease worldwide and projected that the disease will rank first by 2030.1 In practice, its detection, diagnosis, and management often pose challenges for clinicians because of its various presentations, unpredictable course and prognosis, and variable response to treatment.
              Article 0 comments Cited 965 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Yang Zhao
                Zhijun Zhang
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 13 April 2021
                Publication date Collection: April 2021
                Publication date (Electronic): 13 April 2021
                Volume: 66
                Electronic Location Identifier: 103337
                Affiliations
                [a ]Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, Nanjing, Jiangsu 210009, China
                [b ]Department of Psychology, Xinxiang Medical University, Xinxiang, Henan 453003, China
                [c ]Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211100, China
                [d ]School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, Jiangsu 210096, China
                [e ]Mental Health Center Zhejiang University School of Medicine, Hangzhou, Zhejiang 310013, China
                [f ]Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
                Author notes
                [* ]Corresponding author. yzhao@ 123456njmu.edu.cn
                [** ]Corresponding author at: Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, Jiangsu 210009, China. janemengzhang@ 123456vip.163.com
                [1]

                These authors contributed equally to this work.

                Article
                Publisher Item ID: S2352-3964(21)00130-4 Publisher ID: 103337
                DOI: 10.1016/j.ebiom.2021.103337
                PMC ID: 8054154
                PubMed ID: 33862583
                SO-VID: 209e4020-8ed0-4a71-8e30-2497e2f18326
                Copyright © © 2021 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 15 November 2020
                Date revision received : 15 March 2021
                Date accepted : 24 March 2021
                Categories
                Subject: Research Paper

                Keywords: major depressive disorder,biomarker,circular rnas,antidepressive treatment,brain-derived neurotrophic factor,amplitude of low-frequency fluctuation,neuropsychological assessment,competing endogenous rna
                Data availability:
                Keywords: major depressive disorder, biomarker, circular rnas, antidepressive treatment, brain-derived neurotrophic factor, amplitude of low-frequency fluctuation, neuropsychological assessment, competing endogenous rna

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