Biomarkers for Suicidal Behavior: miRNAs and their Potential for Diagnostics through Liquid Biopsy – a Systematic Review

Figures & data

Figure 1. Flow chart of the selection of studies on miRNAs and suicidal behavior.

Only original research papers indexed by PubMed that have investigated miRNAs in suicidal behavior were included in the final selection.

Adapted from [24].

Table 1. Studies of miRNAs and suicidal behavior.

Study (year)	Study subjects	n	Target	Method	Identified miRNA	Predicted target gene or pathway
Gorinski et al. (2019)	MDD suicide victims	16	Dorsal lateral prefrontal cortex (BA9)	Candidate gene analysis: RT-qPCR	miR-30e ↑	ZDHHC21
	Nonpsychiatric control subjects	16
Belzeaux et al. (2019)	MDD patients&duloxetine	112	Whole blood	Genome wide analysis: small RNA-seq	miR-3688 ↑, miR-5695 ↑	Gene ontology leading to “regulation of neurogenesis”
	MDD patients&placebo	125
Wang et al. (2018)	MDD suicide	21	Dorsolateral prefrontal cortex (BA10)	Candidate gene analysis: RT-qPCR	miR-19a-3p ↑	Proinflammation; TNF-α
	Suicide victims & other psychiatric disorders	22
	Nonpsychiatric control subjects	16
	MDD suicide victims	14	Dorsolateral prefrontal cortex (BA10)
	MDD nonsuicide subjects	12
	Healthy control subjects	12
	MDD patients + suicidal ideation	12	Peripheral blood
	Healthy control subjects	12
Roy et al. (2017)	MDD suicide victims	9	Locus coeruleus	Genome-wide analysis: TLDA-based miRNA profiler	miR-17-5p, miR-20b-5p, miR-106a-5p, miR-330-3p, miR-541-3p, miR-582-5p, miR-890, miR-99b-3p, miR-550-5p, miR-1179, all ↑; miR-409-5p, let-7g-3p, miR-1197, all ↓	Multiple genes involved in neurotransmission, associated with psychiatric disorders
	Healthy control subjects	11
Lopez et al. (2017)	MDD suicide victims	32	Ventrolateral prefrontal cortex	Candidate gene analysis: RT-qPCR	miR-146a-5p, miR-146b-5p, miR-24-3p, miR-425-3p, all ↑	MAPK, Wnt, calcium, endocytosis and adherens junction signaling pathways
	Healthy control subjects	20
Torres-Berrio et al. (2017)	MDD suicide victims	24	Prefrontal cortex (BA44)	Candidate gene analysis: RT-qPCR	miR-218 ↓	DCC
	Control subjects	35
	MDD suicide victims	11	Prefrontal cortex (BA44)
	Control subjects	12
Pantazatos et al. (2017)	MDD suicide victims	9	Dorsal lateral prefrontal cortex (BA9)	Genome wide analysis: small RNA-seq	None	None
	MDD nonsuicide subjects	9
	Healthy control subjects	9
Aschrafi et al. (2016)	MDD suicide victims	5	Edinger–Westphal nucleus	Candidate gene analysis: RT-qPCR	miR-326	UCN1
	Control subjects	8
Pantazatos et al. (2015)	MDD suicide victims	9	Dorsal lateral prefrontal cortex (BA9)	Genome wide analysis: small RNA-seq	None	SAT1
	MDD nonsuicide subjects	9
	Healthy control subjects	9
Smalheiser et al. (2014)	Suicide victims	18 (7 MDD, 3 SZ, 8 BP)	Prefrontal cortex (BA10)	Genome wide analysis: TLDA-based miRNA profiler	miR-152, miR-181a, miR-330-3p, miR-34a, miR-133b, miR-224, all ↓; miR-376a, miR-625, both ↑	None stated
	Control subjects	40 (8 MDD, 11 SZ, 6 BP)
	Nonpsychiatric control subjects	15
Lopez et al. (2014)	MDD suicide victims	15	Prefrontal cortex (BA44)	Candidate gene analysis: RT-qPCR	miR-34c-5p, miR-139-5p, miR-195, miR-320c, all ↑	SAT1, SMOX
	Healthy control subjects	16
Maussion et al. (2012)	Low TrkB-T1 expression suicide victims	4	Prefrontal cortex (BA10)	Genome wide analysis: LNA-based miRNA profiler	miR-185* ↑	TrkB-T1
	Normal control subjects	4
	Suicide victims	38	Prefrontal cortex (BA10)	Candidate gene analysis: RT-qPCR
	Control subjects	17
Smalheiser et al. (2012)	Antidepressant-free MDD suicide victims	18	Prefrontal cortex (BA9)	Genome wide analysis: TLDA-based miRNA profiler	miR-142-5p, miR-137, miR-489, miR-148b, miR-101, miR-324-5p, miR-301a, miR-146a, miR-335, miR-494, miR-20b, miR-376a*, miR-190, miR-155, miR-660, miR-130a, miR-27a, miR-497, miR-10a, miR-20a, miR-142-3p, all ↓	Transcription factors and other nuclear proteins, transmembrane and signaling proteins
	Nonpsychiatric control subjects	17

BA: Brodmann area; BP: Bipolar disorder; LNA: Locked nucleic acids; MDD: Major depressive disorder; RNA-seq: RNA-sequencing; RT-qPCR: Quantitative real-time PCR; SZ: Schizophrenia; TLDA: TaqMan RT-qPCR low-density array.

Figure 2. Flow chart of miRNAs, extracellular vesicles or exosomes, and the suicidal behavior, schizophrenia, depression or bipolar disorder study selection.

Only original research papers indexed by PubMed or papers identified in other review papers that have investigated miRNAs and the listed psychiatric disorders were included in the final selection.

Ex. ves.: Extracellular vesicles.

Adapted from [24].

Table 2. Studies of exosomal miRNAs in schizophrenia, bipolar disorder and depression.

Study (year)	Study subjects	n	Tissue	Type of vesicle	Method	Studied/identified miRNA	Predicted target gene or pathway
Banigan et al. (2013)	Schizophrenia	8	Prefrontal cortex (BA9)	Exosomes	Candidate gene analysis: Luminex, RT-qPCR	Bipolar disorder: miR-29c↑, schizophrenia: miR-497 ↑	Wnt signaling, pathogenesis of neoplasms, neurodegenerative diseases and heart disease
	Bipolar disorder	9
	Nonpsychiatric control	13
Du et al. (2019)	Schizophrenia, first episode	49	Peripheral blood serum	Exosomes	Genome-wide analysis: small RNA-seq	miR-206, miR-619-5p, both ↑, has-miR-144-3p ↓	Protein glycosylation, neurotransmitter receptor and dendrite (spine) development, BDNF
	Nonpsychiatric control	46
	Schizophrenia	100	Candidate gene analysis: RT-qPCR
	Nonpsychiatric control	100
Choi et al. (2016)	Bipolar disorder	5	Anterior cingulate cortex tissue (BA24); laser capture micro-dissection of BA24 cortical neurons and glia	Extracellular vesicles	Candidate gene analysis: RT-qPCR	miR-149 ↑; miR-29c, miR-31, miR-15b, miR-497, miR-219	Regulating cell differentiation and cell death, neuropathology
	Nonpsychiatric control	6
Fries et al. (2019)	Bipolar disorder	20	Peripheral blood plasma	Extracellular vesicles	Genome wide: Human miRNA Release 21 Microarray kits	33 nominally significant miRNAs	Axon guidance by netrin and the serotonin receptor pathway
	Nonpsychiatric control	21
Ceylan et al. (2020)	Bipolar disorder	69	Peripheral blood plasma	Exosomes	Genome-wide using RT-qPCR miRCURY LNA miRNA miRNome PCR Panels	miR-484, miR-652-3p, miR-142-3p; all ↓; miR-185-5p ↑	PI3K/Akt signaling, fatty acid biosynthesis/metabolism, extracellular matrix and adhesion pathways
	Nonpsychiatric control	41
Zhang et al. (2017)	Depression	1	Peripheral blood serum	Exosomes	Genome-wide analysis: small RNA-seq	miR-1255a, miR-3161, miR-99a-3p, miR-205-5p, miR-26a-1-3p, miR-139-5p, miR-7849-3p, miR-195-5p, hsamiR-125b-2-3p, miR-664a-3p, let-7c-5p, and miR-197-3p, all ↑; miR-499a-5p, miR-4732-3p, miR-222-5p, miR-1291, miR-668-3p, miR-425-3p, miR-6511a-3p, miR-145-3p, miR-200a-3p, miR-143-3p, miR-196b-5p, miR-99a-5p, miR-144-3p, miR-584-5p, miR-210-3p, miR-183-5p, miR-107, miR-130b-5p, miR-589-5p, miR-1910-5p, all ↓	Upregulated genes: chromatin/histone modification, post-transcriptional regulation of gene expression, neurotrophin signaling pathway, immune system function, inflammation, depression; downregulated genes: apoptotic signaling, oxidation, hypoxia, cell cycle, cellular growth, depression
	Nonpsychiatric control	1

BA: Brodmann area; LNA: Locked nucleic acids; RNA-seq: RNA sequencing; RT-qPCR: quantitative real-time PCR.

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