Abstract
Background
Major depressive disorder (MDD) is one of the most common psychiatric disorders and is a great disease burden. However, its underlying pathophysiology and aetiology remain poorly understood. Available evidence suggests that circulating microRNAs (miRNAs) are associated with MDD, but it is still unknown whether miRNAs can predict subsequent incident MDD.
Methods
In this nested case-control study, a total of 104 individuals, who were free of MDD at baseline, from the Women’s Health in Lund Area (WHILA) cohort were included. Among them, 52 individuals developed MDD (cases) during the 5 years follow-up and 52 individuals did not develop MDD (controls). Plasma expression levels of miR-17-5p, miR-134-5p, miR-144-5p, let-7b-5p and let-7c-5p at baseline were assessed using qRT-PCR. Logistic regression was used to estimate the odds of develo** MDD among individuals with different levels of miRNA expression.
Results
Plasma expression levels of let-7b-5p were significantly lower (p = 0.02) at baseline in cases compared to controls. After adjustment for age and BMI, let-7b-5p was negatively associated with odds for develo** MDD (OR = 0.33, p = 0.03, 95% CI = 0.12–0.91). Moreover, let-7b-5p expression levels showed a trend over time with larger differences between cases and controls for the earlier cases (MDD diagnosis <2 years from baseline) than MDD cases developed later (MDD diagnosis 2–5 years from baseline).
Conclusions
These findings show that lower plasma levels of let-7b-5p are associated with a higher future risk of MDD. Results need to be validated in a large cohort to examine its potential as a peripheral biomarker for MDD.
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Background
Major depressive disorder (MDD) is a medical condition that includes abnormalities in mood, cognition, appetite, sleep, and psychomotor activity [1]. MDD is one of the most common psychiatric disorders worldwide and is currently projected to become the condition with the greatest disease burden after cardiovascular disease (CVD) by 2030 [2]. As of today, clinical suspicion is still the key for the diagnosis of MDD [3] as the underlying pathophysiology and aetiology of depression remain poorly understood [4].
Previous research concerning the pathophysiology of depression has mainly focused on genetic factors that affect the risk of development of depression. However, few genes were found to affect the risk of development of depression [5]. More recently, the attention has shifted to epigenetics, as it has now been generally accepted that depression is a condition caused not only by genetic factors, but also by the influence of environmental factors on gene expression. Epigenetic mechanisms, including histone modifications, DNA methylation, and a newly recognised group of regulators, the non-coding RNAs (ncRNAs), contribute to the regulation of gene expression [6].
The most common ncRNAs are the microRNAs (miRNAs). MiRNAs are a class of endogenous non-coding single-stranded RNAs of approximately 21–23 nucleotides in length. MiRNAs are transcribed in the nucleus and transported to the cytoplasm where they can inhibit gene expression by either promoting messenger RNA (mRNA) degradation or by inhibiting translation through targeting of the 3′ untranslated region (UTR) of the target mRNA (Bartel [7]). MiRNAs are not only present and active in cells, but they are also observed in a stable, cell-free form. A number of studies have detected miRNAs in peripheral bodily fluids such as the whole blood, plasma, and cerebrospinal fluid (CSF) [8].
Over the past decade, circulating miRNAs have already been identified as potential biomarkers in other diseases such as cancer and diabetes [9,10,11,12]. In MDD, some miRNAs have been evaluated in multiple cohorts. MiR-17-5p was found to be significantly upregulated in patients with MDD compared to healthy controls (HC) [13, 14], whereas the expression of miR-134-5p, miR-144-5p, let-7b-5p and let-7c-5p was significantly downregulated [33] examined the ERK1/2 signaling in the frontal cortex and hippocampus of rats showing vulnerability (learned helplessness (LH)) and rats showing resilience (non-learned helplessness (non-LH)) to the development of stress-induced depression. They determined both activation and expression of ERK1 and ERK2 at the transcriptional and translational level and found both protein and mRNA levels to be significantly decreased in hippocampus and frontal cortex of LH rats. These results suggest the involvement of ERK1/2 signaling in generating vulnerability to depression [33]. Thus, downregulation of let-7b-5p leads to a decrease in ERK1/2 signaling, which in turn is associated with an increased risk of MDD development.
This study is the first nested case-control study to explore potential biomarkers for the risk prediction of MDD development. The results of this study were promising, but the limitations of the study must be kept in mind when evaluating the results. Firstly, the sample size was relatively low. The study design, though, required a smaller minimum sample size than what was used in the study. Secondly, cases and controls were unmatched in the study design. This, however, was corrected via adjustments in age and BMI in the statistical analysis. In addition, family history is a major factor concerning the risk assessment of MDD development [34, 35] The effect of family history, however, could not be assessed as this confounder was not included in the WHILA cohort study [18]. Finally, our research indicates that let-7b-5p has the potential as a circulating predictive biomarker of MDD, but functional studies have to be performed in the future to confirm the potential role of miRNAs in MDD risk prediction.
Conclusions
In summary, the findings of this study show that plasma levels of let-7b-5p have the potential as a biomarker of risk prediction for MDD development. Future studies are needed to validate and confirm the results in different cohorts with larger sample sizes.
Availability of data and materials
The datasets generated during and/or analysed during the current study are not publicly available due to privacy concerns; please contact the corresponding author for more information.
Abbreviations
- MDD:
-
Major depressive disorder
- CVD:
-
Cardiovascular disease
- ncRNA:
-
Non-coding RNA
- miRNA:
-
microRNA
- mRNA:
-
Messenger RNA
- UTR:
-
Untranslated region
- CSF:
-
Cerebrospinal fluid
- HC:
-
Healthy control
- SCZ:
-
Schizophrenia
- BD:
-
Bipolar disorder
- CBT:
-
Cognitive behavioural therapy
- RCT:
-
Randomised control trial
- WHILA:
-
Women’s Health in Lund Area
- CPF:
-
Center for Primary Health Care Research
- ICD:
-
International Classification of Diseases
- Ct:
-
Threshold cycle value
- SD:
-
Standard deviation
- BMI:
-
Body mass index
- TG:
-
Triglycerides
- TC:
-
Total cholesterol
- HDL-C:
-
High-density lipoprotein cholesterol
- LDL-C:
-
Low-density lipoprotein cholesterol
- OR:
-
Odds ratio
- CI:
-
Confidence interval
- CNS:
-
Central nervous system
- BBB:
-
Blood-brain barrier
- TRD:
-
Treatment-resistant depression
- KET:
-
Ketamine treatment
- ECT:
-
Electroconvulsive stimulation
- PBMC:
-
Peripheral blood mononuclear cells
- ERK1/2:
-
Extracellular signal-regulated kinase 1/2
- LH:
-
Learned helplessness
- non-LH:
-
Non-learned helplessness
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Acknowledgments
We would like to thank science editor, Patrick Reilly, for the critical reading of the manuscript as well as statistician, Karolina Palmér, for her support in the statistical analysis. The authors wish to thank the County Council in Region Skåne for providing financial and administrative support to this study (ALF grant).
Funding
Open access funding provided by Lund University. This work was supported by grants from the Swedish Research Council to Jan Sundquist (2020–01175) and to Kristina Sundquist (2018–02400) as well as ALF funding from Region Skåne awarded to Kristina Sundquist.
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XW, KS, AAM and JS conceived and designed the study; SR and AH performed the experiments and SR performed the statistical analysis; XW, AAM, JS and AH collected the samples and clinical data. SR wrote the first draft and JS, AH, KS, AAM, SR and XW revised the article, and approved the final version. All authors read and approved the final manuscript.
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This study was performed in-line with the principles of the Declaration of Helsinki. Sample storage and handling procedures were approved by the Ethical Review Board in Lund. Written informed consent was obtained from all subjects.
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Additional file 1: Table S1.
Correlation between peripheral blood biomarkers and let-7b-5p expression levels.
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Roumans, S., Sundquist, K., Memon, A.A. et al. Association of circulating let-7b-5p with major depressive disorder: a nested case-control study. BMC Psychiatry 21, 616 (2021). https://doi.org/10.1186/s12888-021-03621-4
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DOI: https://doi.org/10.1186/s12888-021-03621-4