Evaluation of several micro RNA (miRNA)

Neuroscience Letters 580 (2014) 158–162
Contents lists available at ScienceDirect
Neuroscience Letters
journal homepage: www.elsevier.com/locate/neulet
Evaluation of several micro RNA (miRNA) levels in children and
adolescents with attention deficit hyperactivity disorder
Hasan Kandemir a , Mehmet Emin Erdal b , Salih Selek c,∗ , Özlem İzci Ay b ,
İbrahim Fatih Karababa d , Sultan Basmacı Kandemir e , Mustafa Ertan Ay b ,
Şenay Görücü Yılmaz f , Hüseyin Bayazıt d , Bahar Taşdelen g
a
Department of Child and Adolescent Psychiatry, Faculty of Medicine, Harran University, Şanlıurfa, Turkey
Department of Medical Biology, Faculty of Medicine, Mersin University, Mersin, Turkey
c
Department of Psychiatry, Medeniyet University, Faculty of Medicine, İstanbul, Turkey
d
Department of Psychiatry, Faculty of Medicine, Harran University, Şanlıurfa, Turkey
e
Department of Psychiatry, Balıklı Göl State Hospital, Şanlıurfa, Turkey
f
Department of Medical Biology and Genetics, Faculty of Medicine, Mersin University, Mersin, Turkey
g
Department of Biostatistics, Faculty of Medicine, Mersin University, Mersin, Turkey
b
h i g h l i g h t s
•
•
•
•
miRNA 18a-5p, 22-3p, 24-3p, 106b-5p and 107 levels were decreased in ADHD.
miRNA 155a-5p levels were increased in ADHD.
miR-107 may be a candidate biomarker for ADHD.
Dysregulation of circulating miRNAs may affect ADHD etiology and treatment.
a r t i c l e
i n f o
Article history:
Received 21 April 2014
Received in revised form 15 July 2014
Accepted 31 July 2014
Available online 12 August 2014
Keywords:
ADHD
micro RNA
miRNA
Psychiatry
Child psychiatry
a b s t r a c t
Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent childhood disorders,
although disorders etiology and pathogenesis remains unknown, several theories about ADHD development have been proposed and many researchers believe that it is caused by both genetic and
environmental factors. In this study we evaluated miR18a-5p, miR22-3p, miR24-3p, miR106b-5p,
miR107, miR125b-5p and miR155a-5p levels in child and adolescent ADHD patients. The research sample consisted a group of 52 ADHD patients, and 52 healthy volunteer controls. There was no significant
difference in age and sex between the two groups (p > 0.05). miRNA 18a-5p, 22-3p, 24-3p, 106b-5p and
107 levels were statistically significantly decreased in ADHD patients(p < 0.05). miRNA 155a-5p levels
were increased in patients group (p < 0.05). The positive predictive value (PPV) and negative predictive
value of miR107 was estimated for the cutoff point of 0.4480. PPV was 70% and NPV was 86.5% for the
taken cut off point. There could be a close relationship between levels of circulating miRNAs and ADHD.
If we could understand how the signaling pathways arranged by miRNAs, impact on CNS development,
function and pathology this can improve our knowledge about ADHD etiology and treatment.
© 2014 Elsevier Ireland Ltd. All rights reserved.
1. Objective
Attention-deficit/hyperactivity disorder (ADHD) is characterized by developmentally inappropriate levels of inattention,
hyperactivity, and impulsivity [1]. It is one of the most
∗ Corresponding author.
E-mail address: [email protected] (S. Selek).
http://dx.doi.org/10.1016/j.neulet.2014.07.060
0304-3940/© 2014 Elsevier Ireland Ltd. All rights reserved.
prevalent childhood disorders, occurring in 3–7% of school-aged
children and representing one third to one half of referrals to child
mental health services [2]. ADHD is more common in boys than
girls, with ratios ranging from 3:1 to 10:1 [3]. A large proportion of
children with ADHD are diagnosed with another psychiatric disorder [4]. Overwhelming evidence suggests that ADHD is not a
childhood condition but a lifelong disorder [5].
Although the etiology and pathogenesis of ADHD remain
unknown, several theories have been proposed, and many
H. Kandemir et al. / Neuroscience Letters 580 (2014) 158–162
159
Table 1
Some of the features of the studied miRNAS.
miRNA
Rationale for study
Previous studies
Reference
miR18a-5p
Believed to be involved in DNA damage in
ADHD
Believed to regulate four candidate genes:
BDNF, HTR2C, MAOA, and RGS2
Believed to be related with oxidative stress
which is a potential neurobiological
mechanism in ADHD
Believed to be related with oxidative stress
which is a potential neurobiological
mechanism in ADHD
Believed to be related with minimal brain
change in ADHD
Believed to be related with hypoxia in
ADHD
Believed to be related with prefrontal
cortex pathophysiology ADHD
Altered in DNA damage response
[41]
Found to be altered in Panic Disorder
[22]
Found to be altered in oxidative DNA
damage and lipid peroxidation
[42]
Down regulated in resveratrol treatment
that has antioxidant properties
[43]
Altered in traumatic brain injury and
neurodegenerative diseases
Altered in high altitude sickness
[30]
Altered in depression
[32]
miR22-3p
miR24-3p
miR106b-5p
miR107
miR125b-5p
miR155a-5p
researchers believe it is caused by both genetic and environmental factors [6]. Segregation analysis of data from neurochemical
studies in families comprising genetic, twin, and adoption relationships strongly suggest a genetic etiology [7]. Substantial genetic
influence on the disorder has been identified, with heritability
estimates ranging from 60 to 90% [8]. Studies have identified abnormal regulation of neurotransmitter systems, particularly dopamine
[9]. Preliminary molecular genetic studies have implicated several candidate genes, including the dopamine D2 and D4 (DRD4-7)
receptors as well as the dopamine transporter (DAT-1) [10]. The
presence of the L allele of the serotonin transporter gene 5-HTTLPR
is associated with decreased serotonin levels and increased risk of
ADHD [11].
MicroRNAs (miRNAs) are evolutionally conserved small noncoding RNAs that regulate approximately 30% of human protein
coding gene expression at the post-transcriptional level, and they
play important roles in a wide variety of biological functions
[12]. miRNAs control gene expression by inhibiting translation or
facilitating degradation of their target mRNAs. Computational predictions indicate that thousands of genes could be targeted by
miRNAs in mammals [13]. miRNAs are important for maintaining homeostasis at the neuromuscular junction. They also play an
important role in synaptic plasticity in the central nervous system,
and are involved in memory and mental retardation [14].
The ability of miRNAs to affect the activity of all biological
pathways may underlie some of the difficulties associated with
linking psychiatric disorders to specific causative genes [15]. The
involvement of multiple signaling pathways in psychiatric disease
complicates both the investigation of the underlying biological
causes and efforts to identify effective therapies. Focusing on the
roles of miRNAs in psychiatric diseases may lead not only to an
explanation of the dysregulation of multiple pathways but also to
novel therapies that can target entire gene networks. Perkins et al.
examined the expression of 16 miRNAs in the prefrontal cortex in
subjects with schizophrenia or schizoaffective disorder and found
decreased expression of 15 miRNAs in patients with schizophrenia
[16]. However, although miRNAs have been shown to be particularly abundant in the brain, their role in the development and
activity of the nervous system remains largely unknown. In this
study, we evaluated miR18a-5p, miR22-3p, miR24-3p, miR106b5p, miR107, miR125b-5p, and miR155a-5p levels in children and
adolescents with ADHD. In selection of the miRNAs previous literature pointing out the potential underlying neurobiology (enzyme,
carrier molecule, receptor etc.) of the disease were reviewed and
potential miRNAs from the miRNA database (mirbase.org) that had
both higher target scores and were available in our lab were chosen.
Table 1 shows the features of the studied miRNAs.
[44]
2. Method
The research sample consisted a group of 52 patients from Harran University Faculty of Medicine Research Hospital, Child and
Adolescent Psychiatry Clinic who were referred. The clinic for the
first time and diagnosed with ADHD, and 52 healthy volunteer controls. All patients were diagnosed as ADHD by a child psychiatrist
according to DSM-IV-TR diagnostic criteria and they were treatment naive. In this study, the ADHD module of K-SADS-PL was
used to make the diagnosis of ADHD [17]. Patients with a history
of cardiovascular disorders, epilepsy, diabetes mellitus, psychotic
disorders, pervasive developmental disorders or severe head injury
were excluded. The healthy controls were recruited from healthy
child outpatient unit. After complete description of the study to
the subjects, a written informed consent was obtained from the
parents as well as the assent of children and adolescents. All of
the study procedures were in accordance with the Declaration of
Helsinki. Ethics committee of the Harran University Medical School
approved the trial. Also a semi-structured form was used to detect
several socio demographic and clinical variables of the patients.
The final patient and control groups displayed similar distribution
in age and gender. Study was funded by Harran University Board of
Scientific Research Projects (Funding Number: 12010). This study
was a cross-sectional study and blood sampling was made once
from both controls and patients.
Total RNA was extracted from Peripheral Whole Blood using
Tri-Reagent (Sigma). Reverse transcriptase reactions contained
5 ␮l of extracted total RNA, 50 nM stem–loop RT primer, 1×
RT buffer, 0.25 mM each of dNTPs, 50 unit of modified M-MuLV
Reverse Transcriptase (Thermo Scientific, Vilnius, Lithuania),
25 unit of RiboLock RNase inhibitor (Thermo Scientific, Vilnius,
Lithuania) and nuclease-free water to a total reaction volume
of 15 ␮l. The reaction was performed on an automated Thermal
Cycler (Techne Flexigene, Cambridge, UK). RT-PCR conditions for
30 min at 16 ◦ C, 30 min at 42 ◦ C, 5 min at 85 ◦ C and then held
at 4◦ . Quantitative-Comparative CT (CT ) Real-time PCR was
performed in an ABI Prism 7500 Real-Time PCR System (Applied
Biosystems) using the SDS 2.0.6 software. The specific primers and
fluorogenic ZNATM probes for the microRNAs were designed using
Primer Express 3.0 software (Applied Biosystems) and are listed in
Table 2. The hsa-miR-26b-5p is used as control according to the
Applied Biosystems application note cms 044972 (Applied Biosyshttp://www3.appliedbiosystems.com/cms/groups/mcb
tems:
marketing/documents/generaldocuments/cms 044972.pdf). The
mixed RNAs generated from the control group was used as a
Reference RNA sample. Primers and probes were purchased from
Metabion International AG, D-82152 Martinsried/Deutschland.
160
H. Kandemir et al. / Neuroscience Letters 580 (2014) 158–162
Table 2
Primer/probe sequences of the miR analyzed by quantitative RT–PCR.
microRNA name
Gene ID*
NCBI reference
sequence number**
Primer/probe sequence
hsa-miR-26b-5p
407017
NR 029500.1
hsa-miR-18a-5p
406953
NR 029488.1
hsa-miR-22-3p
407004
NR 029494.1
hsa-miR-24-3p
407012
NR 029496.1
hsa-miR-106b-5p
406900
NR 029831.1
hsa-miR-107
406901
NR 029524.1
hsa-miR-125b-5p
406911
NR 029671.1
hsa-miR-155-5p
406947
NR 030784.1
hsa-miR-26b-5p-RT 5 -GTCGTATGCAGTGCAGGGTCCGAGGTATTCGCACTGCATACGACACCTAT-3
hsa-miR-26b-5p-F 5 -GCCGCTTCAAGTAATTCAGG-3
hsa-miR-26b-5p-PR 5 -FAM-TG(pdC)ATA(pdC)GA(pdC)A(pdC)CTATCC-ZNA4-BHQ-1-3
hsa-miR-18a-5p-RT 5 -GTCGTATGCAGTGCAGGGTCCGAGGTATTCGCACTGCATACGACCTATCT-3
hsa-miR-18a-5p-F 5 -GCCGCTAAGGTGCATCTAGTG-3
hsa-miR-18a-5p-PR 5 -FAM-TG(pdC)ATA(pdC)GA(pdC)CTAT(pdC)TGC-ZNA4-BHQ-1-3
hsa-miR-22-3p-RT 5 -GTCGTATGCAGTGCAGGGTCCGAGGTATTCGCACTGCATACGACACAGTT-3
hsa-miR-22-3p-F 5 -GCCGCAAGCTGCCAGTT-3
hsa-miR-22-3p-PR 5 -FAM-TG(pdC)ATA(pdC)GA(pdC)A(pdC)AGTT(pdC)T-ZNA4-BHQ-1-3
hsa-miR-24-3p-RT 5 -GTCGTATGCAGTGCAGGGTCCGAGGTATTCGCACTGCATACGACCTGTTC-3
hsa-miR-24-3p-F 5 -GCCGCTGGCTCAGTTCAG-3
hsa-miR-24-3p-PR 5 -FAM-TG(pdC)ATA(pdC)GA(pdC)CTGTTCCT-ZNA4-BHQ-1-3
hsa-miR-106b-5p-RT 5 -GTCGTATGCAGTGCAGGGTCCGAGGTATTCGCACTGCATACGACATCTGC-3
hsa-miR-106b-5p-F 5 -GCCGCTAAAGTGCTGACAGT-3
hsa-miR-106b-5p-PR 5 -FAM-TG(pdC)ATA(pdC)GA(pdC)ATCTGCAC-ZNA4-BHQ1-3
hsa-miR-107-RT 5 -GTCGTATGCAGTGCAGGGTCCGAGGTATTCGCACTGCATACGACTGATAG-3
hsa-miR-107-F 5 -GCCGCAGCAGCATTGTACAGGG-3
hsa-miR-107-PR 5 -FAM-TG(pdC)ATA(pdC)GA(pdC)TGATAG(pdC)C-ZNA4-BHQ-1-3
hsa-miR-125b-5p-RT 5 -GTCGTATGCAGTGCAGGGTCCGAGGTATTCGCACTGCATACGACTCACAA-3
hsa-miR-125b-5p-F 5 -GCCGCTCCCTGAGACCCTAAC-3
hsa-miR-125b-5p-PR 5 -FAM-TG(pdC)ATA(pdC)GA(pdC)T(pdC)A(pdC)AAGT-ZNA4-BHQ1-3
hsa-miR-155-5p-RT 5 -GTCGTATGCAGTGCAGGGTCCGAGGTATTCGCACTGCATACGACACCCCT-3
hsa-miR-155-5p-F 5 -GCCGCTTAATGCTAATCGTGAT-3
hsa-miR-155-5p-PR 5 -FAM-TG(pdC)ATA(pdC)GA(pdC) A(pdC)C(pdC)(pdC)TAT-BHQ-1-3
miR-Universal-R 5 -GTGCAGGGTCCGAGGTAT-3
pdC: substitution of C-5 propynyl-dC (pdC) for dC is an effective strategy to enhance base pairing. Using these base substitutions, duplex stability and melting temperatures
are raised by C-5 propynyl-C 2.8◦ per substitution. Zip nucleic acids (ZNA): ZNA probes provide broad flexibility in assay design and represent an effective alternative to
minor groove binder (MGB)- and locked nucleic acid (LNA)-containing oligonucleotides (C. Paris, et al. Zip nucleic acids are potent hydrolysis probes for quantitative PCR.
Nucl. Acids Res. (2010). doi: 10.1093/nar/gkp1218). http://nar.oxfordjournals.org/cgi/content/abstract/gkp1218.
*
http://www.ncbi.nlm.nih.gov/gene.
**
http://www.ncbi.nlm.nih.gov/RefSeq/.
The 25 ␮l PCR included 3 ␮l RT-PCR product, 12.5 ␮l of 2× TaqMan
Universal PCR Master Mix (Applied Biosystems), 900 nmol of
each primer (Primer F and Universal Primer R) and 200 nmol
TaqMan® probe. The reactions were incubated in a 96-well plate of
preincubation at 50 ◦ C for 2 min and at 95 ◦ C for 10 min, followed
by 40 cycles at 95 ◦ C for 15 s and at 60 ◦ C for 90 s. Amplifications
and analysis were performed in an ABI Prism 7500 Real-Time PCR
System (Applied Biosystems), using the SDS 2.0.6 software for
allelic discrimination (Applied Biosystems). All reactions were run
in triplicate. Relative expression of miRNA was calculated using
2−ct method. Higher ct values indicate lower expression
rates.
The data were processed and analyzed using the statistical
package SPSS-11.5 for Windows. Normality of 2−DDCT values was
checked by Shapiro Wilk test. In case of non-normal distribution, 2−DDCT values were expressed as median, first quartile (25th
percentile), third quartile (75th percentile), and the comparison
between groups was performed using the Mann–Whitney test.
Box-plot graph was used to represent data distribution of miR18a5p, miR22-3p, miR24-3p, miR106b-5p, miR107, miR125b-5p and
miR155a-5p variables according to the groups. Significant differences (two-tailed p) less than 0.05 were regarded as significant.
3. Results
This study included 52 ADHD subjects with a mean age of
10.09 ± 2.36 years (range, 7–17 years) and 52 control subjects with
a mean age of 10.92 ± 2.96 years (range, 7–17 years). No statistically
significant differences were detected in age and sex between the
two groups (p > 0.05; Table 3). The levels of MiR18a-5p, miR22-3p,
miR24-3p, miR106b-5p, and miR107 were significantly decreased
in the ADHD subjects compared with controls (p < 0.05). Additionally, decreased levels of miR-125b levels were observed, but this
trend was not statistically significant (p > 0.05). MiR155a-5p levels
were increased in the patient group (p < 0.05; Table 4). The receiver
operator characteristic (ROC) graph was drawn for miR107. The
positive predictive value (PPV) and negative predictive value of
miR107 was estimated for the cutoff point of 0.4480. PPV was 70%
and NPV was 86.5% for the taken cut off point.
4. Discussion
To our knowledge, this is the first study to evaluate miRNA levels
in ADHD subjects; therefore, we compared our results with those in
other psychiatric disorders. We found decreased levels of miR18a5p, miR22-3p, miR24-3p, miR106b-5p, and miR107 in ADHD
subjects compared with controls. In a study examining the relationship between miR-18a and endogenous glucocorticoid receptor
protein expression in rats, Uchida and Vreugdenhil suggested that
levels of miR-18a could be an important susceptibility mechanism
for stress-related disorders [18,19]. Recent studies reported genetic
evidence for the association of the hypothalamic–pituitary–adrenal
(HPA) axis and long-term effects of glucocorticoid in patients with
ADHD [20,21].
Muinos et al. reported that miR22 was associated with panic
disorder and that it regulated several candidate genes and related
pathways involved in anxiety. In his study miR-22 was the miRNA
with the highest number of functional targets, with four genes
being potentially repressed by this miRNA: the neurotrophic factor BDNF, the serotonin receptor HTR2C, monoamine oxidase
A—MAOA—those which are also potential targets in neurobiology
of ADHD [22]. A history of childhood ADHD features among adults
with panic disorder has been reported [23]. Moreau et al. reported
dysregulation of miR22 in schizophrenia and bipolar disorders [24].
Dysregulation of miR106b and miR24 levels has been reported
in some psychiatric disorders including schizophrenia, bipolar disorder, and autism [16,24–27]. Sarachana et al. found that miR106b
and miR107 levels were associated with autism [28]. Nelson et al.
found decreased miR107 levels in patients with Alzheimer disease [29]. miR107 has been studied in traumatic brain injury,
H. Kandemir et al. / Neuroscience Letters 580 (2014) 158–162
161
Table 3
Sociodemographic and clinical characteristic of patients.
ADHD (n = 52)
Sex: male/female (n)
Age: mean ± SD (year)
Age range(year)
ADHD subtypes (N)
Attention deficit
Hyperactivity/impulsivity
Combined
42/10
10.09 ± 2.36
7–17
Control (n = 52)
Comparison
p = 0.174 (x2 = 1.846)
p = 0.119 (t = −1.574)
36/16
10.92 ± 2.96
7–17
5
3
44
Table 4
Comparison of miRNA levels* .
Controls
hsa-miR-18a-5p
hsa-miR22-3p
hsa-miR-24-3p
hsa-miR-106b-5p
hsa-miR-107
hsa-125b-5p
hsa-miR-155-5p
*
Patients
p Value
Median
25–75%
Median
25–75%
2.1366
0.7884
1.1988
1.7052
1.8769
1.9763
0.3331
1.3001–3.6987
0.2737–1.9878
0.5765–2.1922
1.1714–2.7165
0.7394–3.6685
0.9575–4.6276
0.1693–0.7744
0.3264
0.1939
0.4239
0.7376
0.2162
1.7163
0.9312
0.1266–1.1465
0.0850–0.8438
0.1951–1.9272
0.3246–1.9879
0.0569–0.5804
0.7222–6.4082
0.2169–2.5472
<0.001
0.001
0.025
0.001
<0.001
0.687
0.011
Higher ct values indicate lower expression rates.
neurodegenerative disease, and frontotemporal dementia [30]. One
study reported upregulation of mir107 expression in the postmortem brains of patients with schizophrenia [31].
We found increased miR155a-5p levels in patients with ADHD
compared with controls. A previous study reported miR155 dysregulation in patients with depression [32]. Additionally, increased
miR155 levels were reported in patients treated with lithium [33].
We observed decreased miR125b levels in ADHD subjects
in our study, but this decrease was not statistically significant.
Eipper-Mains reported an association of miR125 levels and addiction disorders in mice [34]. Additionally, miR125-5p levels have
been studied in autism, Huntington’s disease, and Alzheimer
[28,35–37].
Recent studies have revealed that aberrant expression of circulating miRNAs suggests potential diagnostic biomarkers of disease
[38]. There are 17 studies of neuropsychiatric disorders such as
Schizophrenia, Bipolar Disorder and Alzheimer’s Dementia showing peripheral miRNA changes reflecting the central nervous
system pathology in those diseases [39]. On the other hand, since
psychiatric disorders including ADHD are syndromes that does not
only affect the brain but also most of the body, peripheral changes
are expected as well. For example, in ADHD peripheral oxidative
stress biomarkers are shown to be altered as in most of the other
neuropsychiatric disorders [40]; however, no blood test for ADHD
has yet been developed. Our study suggested that miR107 levels
below 0.4480 were highly predictive (PPV:70.6) of ADHD, with
a negative predictive value (NPV) of 86.5%. A close relationship
between levels of circulating miRNAs and the presence of ADHD
may exist regardless of family history. Understanding the signaling
pathways affected by miRNAs in CNS development, function, and
pathology could lead to improved therapies for treating heterogenic diseases.
Our study had several limitations, including the sample size,
cross-sectional design and the limited number of miRNA types.
Moreover, the lack of studies in the literature regarding ADHD and
miRNAs prevents the comparison of our findings with previous
studies. Despite these limitations, we believe our findings provide
important groundwork for future studies.
In conclusion, understanding the dysregulation of circulating
miRNA levels may improve our knowledge about ADHD etiology
and treatment. miR-107 may reflect disease status and may be a
candidate biomarker for ADHD diagnosis. Our results should be
regarded as preliminary until they are replicated.
Role of funding source
Our study has been supported by Harran University Coordination of Scientific Research Projects (Funding Number: 12010).
The English in this document has been checked by at least two
professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/certificate/XTjhHb.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.neulet.
2014.07.060.
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