# Small Nucleolar RNAs and the Brain: Growing Evidence Supporting Their Role in Psychiatric Disorders

Juliette Salles, Rixing Lin, Gustavo Turecki

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Juliette Salles, Rixing Lin, Gustavo Turecki. Small Nucleolar RNAs and the Brain: Growing Evidence Supporting Their Role in Psychiatric Disorders. Biological Psychiatry Global Open Science, 2025, 5 (2), pp.100415. 10.1016/j.bpsgos.2024.100415. hal-05515369

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# Small Nucleolar RNAs and the Brain: Growing Evidence Supporting Their Role in Psychiatric Disorders

Juliette Salles, Rixing Lin, and Gustavo Turecki

## ABSTRACT

Noncoding RNAs comprise most of the transcriptome and represent an emerging area of research. Among them, small nucleolar RNAs (snoRNAs) have emerged as a promising target because they have been associated with the development and evolution of several diseases, including psychiatric disorders. snoRNAs are expressed in the brain, with some showing brain-specific expression that indicates specific roles in brain development, function, and dysfunction. However, the role of snoRNAs in conditions that affect the brain needs further investigation to be better understood. This scoping review summarizes existing literature on studies that have investigated snoRNAs in psychiatry and offers insight into potential pathophysiological mechanisms to be further investigated in future research.

https://doi.org/10.1016/j.bpsgos.2024.100415

## SMALL NUCLEOLAR RNA EXPRESSION AND ROLES

Most of the transcriptome of the genome consists of non-coding RNAs (ncRNAs) (1). NcRNAs can be divided into different classes, broadly based on their size (2) or their functions (3,4).

Small nucleolar RNAs (snoRNAs) belong to the class of intermediate size (60- to 300-nucleotide-long) ncRNAs. They are found in all eukaryotic genomes, even if their organization and regulation has changed considerably throughout evolution (5), and their number increases with the complexity of the organism. For example, in the yeast *Saccharomyces cerevisiae*, 64 transcription units encode 76 snoRNAs, and 731 reads are found in *Potamochoerus porcus*, whereas in humans, a recent update of the snoRNA database lists 2123 predicted snoRNAs (6), 505 of which have been validated by sequencing in human skeletal muscle, liver, testis, and brain tissues (7,8). In addition, snoRNAs could be located in unfavorable loci, defined by the absence of a nearby active promoter and/or the absence of flanking sequences that allow the formation of a terminal stem. This explains why most annotated vertebrate snoRNAs are not expressed; in fact, most vertebrates are predicted to have only between 13% and 45% of expressed snoRNAs (9). Among the expressed snoRNAs, only a small fraction of the snoRNA gene is not inserted in the host gene and is expressed from independent promoters. The process of snoRNA transcription is shown in Figure 1A. Their canonical function is to facilitate the pseudouridylation and 2'-O-methylation of ribosomal RNAs (rRNAs) (10,11), as described in the Supplement.

snoRNAs are divided in 2 main classes: the C/D box snoRNAs (SNORDs) and the H/ACA box snoRNAs (SNORAs). SNORDs are characterized by the presence of 2 conserved

sequence motifs, box C (UGAUGA) and box D (CUGA), near the 5' and 3' termini, respectively (Figure 1B). snoRNAs associate with protein to form snoRNA-ribonucleoprotein complexes (Figure 1C). snoRNA-ribonucleoprotein complex associations and function are described in the Supplement.

Most snoRNAs are expressed uniformly across tissues, while 18% of snoRNAs are enriched in specific tissues (7). Interestingly, the most tissue-specific snoRNAs are found in the brain and reproductive tissues; 10% of the snoRNAs are enriched in the brain (Box 1) (7). Another study noted that the evolutionary changes in frontal cortex expression of snoRNAs across humans, chimpanzees, rhesus monkeys, and mice shows a substantial divergence of snoRNA expression levels among the 4 mammalian species at the individual gene level. Of the 183 snoRNA genes present in the 4 species and expressed in brain, 83 (44%) showed divergent expression among species, but the bias toward evolutionary acceleration in the human evolutionary lineage was moderate (12). However, the example of the divergence of *SNORA29* snoRNA expression in the human lineage is particularly striking. *SNORA29* maintains high expression levels in mice, macaques, and chimpanzees but decreases significantly in humans. This decrease could be caused by the reduced stability of its secondary structure. However, the authors specified that these results do not provide information about the role of *SNORA29* in the evolution of human-specific cognitive features (12). As with other RNA types, the degree of snoRNA expression divergence among species is largely proportional to phylogenetic divergence. This may suggest that snoRNA expression divergence merely reflects the accumulation of genetic divergence between species and has no functional effect. However, this hypothesis is difficult to reconcile with the essential role of snoRNA in modifying highly conserved functional RNA molecules. Therefore, the

SEE COMMENTARY NO. 100447
<figure><img src="image_2.png" /><figcaption>**Figure 1.** (A) Transcription, processing. snoRNA genes are predominantly located within gene introns and released from the host gene precursor messenger RNA by splicing (5); the expression can be regulated independently from the level of the host RNA or other snoRNAs within the same transcription unit (4). RNA polymerase II transcribes the majority of independently transcribed snoRNA genes, but most of the information regarding the promoters of these genes comes from yeast (96), and the structure of promoters is largely unknown in humans although some progress has been made through bioinformatic analysis (97). Once their host intron is excised, the snoRNAs are embedded in RNAs without a 5' cap or a polyA tail. snoRNA may also be associated to long noncoding RNAs; some of them are 5' snoRNA capped and 3' polyadenylated carrying a snoRNA at both ends or only at the 5' end, respectively (98). These snoRNAs protect the inner sequence from degradation, thus creating long noncoding RNA-snoRNA hybrids (99). During transcription, the 5' m7G cap is cotranscriptionally added to the nascent molecule and then removed (100) or converted to a TMG cap (101). A 3' end processing is also required for final maturation. (B) Overview of structural canonical SNORD with C box and a D box motif located close to the terminal stem and additional internal C' and D' boxes (location of methylation from Box D/D') and canonical SNORA with 2 stem loop structures with an internal H box motif and an ACA box motif at the 3' end (location of pseudouridylation [NΨ]) at the base of the hairpins). (C) Assemblage of protein factors on the snoRNA (boxes C/D and H/ACA snoRNPs) that protect snoRNAs from exonuclease degradation (102). rRNA, ribosomal RNA; SNORA, H/ACA box snoRNA; SNORD, C/D box snoRNA; snoRNA, small nucleolar RNA; snoRNP, snoRNA-ribonucleoprotein complex.</figcaption></figure>

authors proposed that brain snoRNAs play a more dynamic role in RNA-based regulatory and functional networks than is currently recognized (12).

Beside their canonical function, alternative roles have been described for snoRNAs. Notably, snoRNAs have been shown to interact with messenger RNAs (mRNAs). As examples, SNORD83B was found to stabilize the levels of target mRNAs (13), while SNORD115 was shown to promote alternative

splicing of the serotonin receptor 2C (HTR2C) (14) and to compete with adenosine deaminases acting on RNA enzymes that otherwise catalyze mRNA editing (15). Furthermore, SNORD27 was shown to direct splicing of the E2F7 transcription factor (16), and SNORD88C was shown to regulate alternative splicing of FGFR3 (17). SNORD50A was reported to inhibit 3' mRNA processing for a subset of transcripts (18). Increasing numbers of reports have identified snoRNAs

**Box 1. Brain Enriched snoRNAs**

<table><tr><td>SNORD3</td><td>SNORD115-15</td><td>SNORD115-25</td><td>SNORD115-36</td><td>SNORD115-45</td></tr><tr><td>SNORD108</td><td>SNORD115-16</td><td>SNORD115-26</td><td>SNORD115-37</td><td>SNORD115-48</td></tr><tr><td>SNORD109B</td><td>SNORD115-17</td><td>SNORD115-29</td><td>SNORD115-38</td><td>SNORD115-5</td></tr><tr><td>SNORD115</td><td>SNORD115-19</td><td>SNORD115-3</td><td>SNORD115-39</td><td>SNORD115-6</td></tr><tr><td>SNORD115-1</td><td>SNORD115-2</td><td>SNORD115-30</td><td>SNORD115-4</td><td>SNORD115-8</td></tr><tr><td>SNORD115-10</td><td>SNORD115-20</td><td>SNORD115-31</td><td>SNORD115-40</td><td>SNORD115-9</td></tr><tr><td>SNORD115-11</td><td>SNORD115-21</td><td>SNORD115-32</td><td>SNORD115-41</td><td>SNORA35</td></tr><tr><td>SNORD115-12</td><td>SNORD115-22</td><td>SNORD115-33</td><td>SNORD115-42</td><td></td></tr><tr><td>SNORD115-13</td><td>SNORD115-23</td><td>SNORD115-34</td><td>SNORD115-43</td><td></td></tr><tr><td>SNORD115-14</td><td>SNORD115-24</td><td>SNORD115-35</td><td>SNORD115-44</td><td></td></tr></table>

The list has been reproduced with permission from supplementary data in Fafard-Couture *et al.* (7).
Role of snoRNAs in Psychiatric Disorders

interacting with proteins. An example is the interaction of
snoRNAs and PARP-1, a nuclear enzyme implicated in DNA
damage repair. SNORA73A, SNORA73B, and SNORA74A can
bind to PARP-1, leading to enhanced ribosome biogenesis,
protein translation, and cell proliferation (19). Other alternative
roles for snoRNAs include facilitating RNA or DNA methylation
by guiding methyltransferases to mRNA or DNA. Accordingly,
in previous work, we demonstrated that SNORD90 and a
microdeletion encompassing 2 snoRNAs, SNORD109A and
SNORD116, act by promoting RNA and DNA methylation,
respectively (20–22). SNORD90 was found to play a role as an
m6A RNA methylation inducer. In addition, in a cellular model
of induced pluripotent cells differentiated into neurons from
this patient with SNORD116 microdeletion compared to con-
trol, we also found differential methylation and expression,
especially in the SLC6A3 gene involved in dopaminergic
clearance (21). SNORD116 microdeletion has been described
as part of the minimal region associated with the neuro-
developmental disorder Prader-Willi syndrome (23). Within this
region, SNORD116 is especially interesting because Snord116
knockout mice present with a decreased expression of the
proprotein convertase gene PCSK1 responsive for pro-
hormone maturation including oxytocin (24), but this was not
confirmed in another study (25). Furthermore, research in-
dicates that levels of Snord116 affect the expression pattern of
*Nlgn3* and *Dgkk*. For *Nlgn3*, this effect could be the result of 2
processes: interaction with *Nlgn3* exon 3 in the close vicinity of
the splicing site could decrease its usage if it occurred on the
pre-mRNA and/or the RNA isoforms that possess a Snord116
hybridization site may be destabilized by the interaction, as is
likely the case for *Dgkk*. Both of these genes are important for
brain function (26). In particular, *Nlgn3* is involved in the
signaling of oxytocin in dopaminergic cells (27).

snoRNA in Psychiatric Disorders

The role of snoRNAs has been investigated in several human
illnesses (28), such as cancer (29–32), lung diseases (33),
cardiovascular diseases (34), neurological disorders (35), and
treatment response (36–38). In the field of psychiatry, there is
already a great deal of interest in ncRNA, particularly micro-
RNA (miRNA) (39–43). However, to date, relatively few studies
have focused on snoRNAs in psychiatric disorders, a surpris-
ing fact considering their role and relative importance in the
brain. In this review, we summarize the current findings of
snoRNAs related to psychiatric disorders and discuss the im-
plications and future directions for this field by using a method
described in the Supplement.

Studies in Autism Spectrum Disorder

Seven studies have investigated an association between
snoRNA expression and autism spectrum disorder (ASD). Three
of these studies were conducted using blood transcriptomes
(44–46), while the others focused on transcriptomes of post-
mortem brain tissue (47–51). A total of 80 different snoRNAs
(31 SNORAs and 49 SNORDs) were identified as being asso-
ciated with ASD in these studies. Among the 80 snoRNAs
identified in these studies, 28 were found in more than 1 study,
and 4 were detected in both blood and brain tissue (SNORA26,
SNORA46, SNORA63, and SNORA73A). In blood, SNORA26,

SNORDA46, and SNORA63 were upregulated in a group of ASD
patients with severe symptoms versus mild symptoms (45)
while they were downregulated in well-defined samples of the
superior temporal gyrus in patients with ASD compared with
control participants (51). In blood, SNORA73B was upregulated
in a group of ASD patients with severe symptoms versus mild
symptoms (45), and its expression increased with age in the
superior temporal sulcus of participants with ASD (47).

A study used transcriptomic profiling to directly compare
laser capture microdissected neurons from anatomically well-
defined samples of the superior temporal gyrus, including 59
participants with ASD and 32 control participants who ranged in
age from 2 to 73 years. From this analysis, 52 of the 83 neuron-
expressed snoRNA genes were upregulated in ASD neurons,
and 31 were significantly downregulated, whereas dysregula-
tion of snoRNAs was not observed in bulk tissue. The authors
also found that both ribosome and spliceosome components
were among the most downregulated in ASD, which is inter-
esting considering the role of snoRNAs in the modification and
maturation of rRNAs and small nuclear RNAs (snRNAs).
Because snoRNAs and snRNAs are known to be critical regu-
lators of alternative splicing, and splicing alterations are thought
to be implicated in ASD and may be observed in the laser
capture microdissection-captured neurons, they examined al-
terations in splicing events associated with snoRNA dysregu-
lation. They identified 835 gene loci in neurons where significant
correlations between snRNA expression and intron splicing
alterations were observed. Of these 835 loci, 196 were signifi-
cantly dysregulated in ASD neurons. Several intron clusters
correlated with multiple snoRNAs and corresponded to genes
involved in synaptic functions. Therefore, they hypothesized
that coordinated downregulation of multiple snoRNAs correlate
with increased dysregulation of local splicing events in neurons
from patients with ASD (51).

Studies in Schizophrenia

Four studies have explored associations between snoRNA
expression and schizophrenia (SCZ). Most of these studies
were performed in postmortem brain tissue (50,52,53), whereas
only 1 study used blood samples (54). A total of 25 snoRNAs
were identified from all these studies, including 5 SNORAs and
20 SNORDs. SNORA7B and SNORD115-10 were found in more
than 1 study, with SNORD115-10 being the only one to be found
in both brain and blood. It was found to be upregulated in the
anterior cingulate cortex of male patients with SCZ versus fe-
male patients (53) and hypermethylated in blood from patients
with SCZ versus control participants (54). Interestingly,
SNORD115 and CRHR1 were previously detected together
among 19 genes that were ranked as plausible candidates for
psychotic disorder and obesity (55). The SNORD115 gene (also
known as HBII-52) was found to regulate the alternative splicing
of the 5-HT2C receptor (HTR2C) by binding to a silencing
element in exon Vb (14). In addition to regulating alternative
splicing, SNORD115 affects RNA editing, an essential mecha-
nism for the generation of HTR2C (56), and was shown to inhibit
the efficiency of RNA editing of HTR2C (57). Moreover, an
adverse maternal environment was found to significantly in-
crease the expression of total Htr2c in the hippocampi of male
mouse offspring associated with increased Snord115 levels
(58). A study found that the firing rate of dopaminergic neurons in the ventral tegmental area and serotonergic neurons in the dorsal raphe nucleus was significantly increased in *Snord115* knockout mice, but this dysfunction was not associated with defects in behavioral abnormalities (binge eating, conditioned place preference for cocaine, or compulsive behavior) (59). Finally, one study challenged these results, finding modest region-specific changes in *HTR2C* RNA editing profiles, while *HTR2C* alternative RNA splicing was unchanged (60).

Ketchesin *et al.* (52) investigated disruptions in sleep and circadian rhythms, which are known to be associated with the onset or exacerbation of psychotic symptoms, in patients with psychosis (including SCZ, schizoaffective disorder, and bipolar disorder with psychosis). They conducted an investigation by performing RNA sequencing and rhythmicity analyses to investigate diurnal alterations in gene expression in human postmortem striatal subregions (nucleus accumbens, caudate, and putamen) in 36 participants with psychosis (primarily SCZ) relative to the same number of control participants. Before this study, they conducted an investigation of participants without psychiatric or neurological disorders and identified snoRNAs as the top rhythmic transcripts in the nucleus accumbens (61). The second study yielded consistent results for control participants, indicating that snoRNAs were among the top 100 rhythmic transcripts in the nucleus accumbens of control participants. However, this enrichment was not observed in SCZ. snoRNAs are known to chemically modify other RNAs, thereby regulating processes such as ribosomal biogenesis, RNA splicing, and RNA editing. The loss of rhythmicity in snoRNAs suggests potential circadian dysregulation of regulation processes associated with snoRNAs such as ribosomal biogenesis, RNA splicing, or RNA editing (52). In addition, snoRNAs were previously found to be involved in diurnal rhythm, and DNA methylation that is responsive to daily rhythms was modified in a mouse *Snord116* deletion model (22).

## Studies in Bipolar Disorder, Major Depressive Disorder, Posttraumatic Stress Disorder, and Suicide

One study indicated that snoRNAs may be associated with bipolar disorder. It examined genotypes and RNA sequencing in brain samples (frontal and temporal cortex) and found that *SNORD3B-2* was upregulated in this population (62).

Three studies have highlighted snoRNAs associated with major depressive disorder (MDD), 2 of which were conducted using brain tissue (63,64) and 1 was conducted using both brain tissue and blood (20). However, no overlap was observed between the results of these studies. Our team quantified snoRNA expression by small RNA sequencing in human postmortem lateral habenula samples of individuals with MDD and psychiatrically healthy control participants, and *SNORA69* showed increased expression in MDD and was technically validated via reverse transcriptase-quantitative polymerase chain reaction. In addition, *Snora69* was upregulated in the mouse lateral habenula and peripheral blood in an unpredicted chronic mild stress mouse model of depression. *SNORA69* guides pseudouridylation onto 5.8S and 18S rRNAs. We quantified the relative abundance of pseudouridines on 5.8S and 18S rRNA in human postmortem lateral habenula samples and found increased abundance of pseudouridines in the MDD

group. The relevance of this observation to the psychopathology of MDD remains uncertain. It is possible that changes to rRNA pseudouridylation could affect binding to transfer RNA and mRNA, potentially impacting translation and proteomic profiles in MDD. However, further studies are necessary to confirm this hypothesis (64).

Only one study has investigated posttraumatic stress disorder (PTSD): In a transcriptome-wide expression study in whole blood samples of 324 World Trade Center responders (201 never PTSD, 81 current PTSD, 42 past PTSD), *SNORD54* and *SNORD46* were downregulated in patients with current PTSD compared with World Trade Center responders without PTSD (65).

A genome-wide study examined gene expression in the amygdala, hippocampus, prefrontal cortex, and thalamus in postmortem brain samples from 20 individuals who died by suicide and 7 control participants and found that, in the suicide group, *SNORA13* and *SNORA62* were upregulated in all brain regions; *SNORD114-31*, *SNORD114-15*, and *SNORD114-10* were downregulated in the amygdala and hippocampus; and *SNORA23* was upregulated in the prefrontal cortex (66). Another study performed RNA sequencing in the rostral anterior cingulate cortex of 26 people with depression who died by suicide and 24 matched control participants and found that *SNORD3C* was upregulated in MDD (67).

Therefore, the findings on snoRNA expression in mood disorders, including suicide, are not consistent across reports. This could be explained by differences in the tissues used for analysis. This discrepancy could also be related to the lack of specification of stressful life events, especially early-life stress (ELS). ELS produces dysregulations that occur at different biological levels. Evidence suggests that the hypothalamic-pituitary-adrenal axis and the serotonergic, dopaminergic, neurotrophin, and oxytocin systems may play a role in mediating ELS and MDD (68). Evidence also suggests that ELS induces changes in miRNA function via a complex interaction of genes relevant to the hypothalamic-pituitary-adrenal axis as well as other neuroendocrine signaling systems (69). Therefore, this parameter should also be investigated for snoRNA.

## Studies of Association With Psychiatric Treatment Response

Our team examined snoRNA expression using sequencing data generated from peripheral blood samples collected from 3 independent antidepressant clinical trials involving individuals diagnosed with MDD who were treated with antidepressants (20). *SNORD90* was the only snoRNA consistently upregulated after antidepressant treatment across all 3 independent cohorts. To go further, we investigated *SNORD90* expression in human postmortem anterior cingulate cortex, which was upregulated in individuals who died during a depressive episode but were taking antidepressants. We observed the same pattern of expression in both neuronal and nonneuronal cell types, which suggests that antidepressants do not upregulate *SNORD90* in a cell type-specific manner. The expression of *Snord90* in a paradigm designed to model depressive-like behaviors in mice showed a specific upregulation of *Snord90* in the anterior cingulate cortex of mice that underwent the depression paradigm followed by antidepressant
administration, whereas the depression paradigm or antidepressant administration alone did not alter the expression of *Snord90*. In addition, we treated human neuronal cells derived from human induced pluripotent stem cells and differentiated to a monoaminergic phenotype with several psychotropic drugs and observed that *SNORD90* expression was upregulated exclusively by antidepressant drugs. In human neural progenitor cells, we found that overexpressing *SNORD90* resulted in a decrease in NRG3 expression, and knocking down *SNORD90* resulted in an increase of NRG3 expression. We identified a sequence motif for RBM15B, and we hypothesized that *SNORD90* likely acts as a guide RNA for RBM15B and its associated m6A writer complex. We performed m6A immunoprecipitation quantitative polymerase chain reaction and observed an increase in m6A abundance on NRG3 following *SNORD90* overexpression. We knocked down RBM15B expression and found that RBM15B knockdown followed by *SNORD90* overexpression blunted the increase of m6A levels on NRG3. This result supported that *SNORD90* guides m6A modifications onto NRG3. In a mouse model, NRG3 expression was associated with an increase in spontaneous excitatory postsynaptic current frequency following *Snord90* overexpression. This indicated that *SNORD90* mediated downregulation of NRG3 and has implications for glutamate neurotransmission, which translates to behavioral changes such as anxiolytic and antidepressive-like behavior (20).

The snoRNAs associated with psychiatric disorders are summarized in Table 1.

## LIMITATIONS OF AND NOTABLE RESULTS FROM THE CURRENT LITERATURE

The current review of published studies revealed several limitations. Firstly, only a limited number of studies have reported on the expression of snoRNAs in psychiatric disorders.

Secondly, in instances where multiple studies were conducted on the same disorders, only a limited number of snoRNAs were found to be shared between the studies and/or between different types of samples (blood and brain). Furthermore, these identified snoRNAs were not previously known to be involved in pathophysiological mechanisms associated with psychiatry, with the exception of *SNORD115*, which was identified in various studies and tissue samples regarding SCZ, as previously mentioned.

Another limitation is that studies performed using human postmortem brain tissue are likely to have included participants who were taking medication. This parameter should be taken into account in the analysis of snoRNA expression.

Another limitation of most of the studies reviewed here is that they were not specifically focused on snoRNA expression but rather on large-scale transcriptomic analyses. As a result, they may have lacked the required coverage to study all snoRNAs; also, most of the reports were descriptive, and with a few exceptions illustrated in Figure 2 (20,51,52,64), they did not directly include mechanistic work.

## FUTURE DIRECTIONS

As a potential future direction, the use of snoRNAs as biomarkers could be considered, as it was previously considered

for miRNAs in psychiatry (70,71). However, biomarker research is challenging in psychiatry due to the inaccessibility of sampling brain tissue from patients. One emerging and promising avenue is also the investigation of biomarkers in exosomes, which are a class of extracellular vesicles (EVs) of endocytic origin accessible in biofluids such as saliva, urine, and plasma. EVs can cross the blood-brain barrier and carry cargo and display membrane proteins that allow differentiation and identification of tissue of origin, including brain (72). In the brain, EVs are involved in processes such as synaptic plasticity, neuronal stress response, cell-to-cell communication, and neurogenesis (73). These mechanisms have previously been implicated in psychiatric disorders, leading to the hypothesis that EVs may be involved in psychiatric phenotypes (74,75). EVs contain predominantly shorter RNA species (≤200 nucleotides), including small RNA biotypes (miRNA, snoRNA, snRNA, Y-RNA, vault RNA, and others) (76). Despite the scarcity of data about snoRNAs in this field, some of them have previously been found in exosomes and associated with human diseases. Thus, studies have found a sufficient stability of snoRNA and effect size to consider the use of snoRNA in exosomes as biomarkers. For example, *SNORD3H*, *SNORD1C*, and *SNORA74D* were found as biomarkers of breast cancer in plasma exosomes (77). *SNORD57* and *SNORDB1771* were found to be downregulated during periodontitis and recovered to healthy levels after treatment in plasma exosomes (78). *SNORD115* and *SNORD116* showed high discriminatory power to differentiate Alzheimer's disease samples from control samples in plasma exosomes (79). Together, these studies demonstrated the stability and abundance of exosomal snoRNAs. This is not surprising because small nucleic acids, such as microRNAs, are known to be very stable (80). There are also a few published data from psychiatric cohorts to assess clinical prediction in this specific field. In addition to the question of stability, it is also a question of abundance and methods used for detection, because for rare RNAs to be discovered in exosomes, the option of deep RNA sequencing should be the gold standard. The increase in sequencing depth and read length allowed by the new technologies will certainly contribute to the emergence of new results.

Most of the studies reported to date looked at snoRNA expression in blood, which did not allow exploration of the pathophysiological hypothesis. Nevertheless, some focused on snoRNA expression in specific brain areas that were chosen because of their implication in the pathophysiology of the disorder. snoRNA expression in the superior temporal sulcus is relevant for ASD because this region supports multimodal integration for social perception and cognition (81). snoRNA expression in the lateral habenula is relevant for MDD because this region plays a role in reward processing, learning, and goal-directed behavior (82), and snoRNA in the anterior cingulate cortex is relevant for SCZ because neurobiological abnormalities of this area have been reported in stages of the disease (83). The regional specificity of these findings brings more accuracy to develop mechanistic hypotheses. In addition, within these specific areas, single-cell or single-nucleus sequencing, which are available in psychiatric research (84), would also allow specification of cell type involvement in the pathology of psychiatric disorders. In addition, more
<table><caption>Table 1. Summary of snoRNAs Found in Psychiatric Studies</caption><thead><tr><th>snoRNA</th><th>Sample</th><th>Psychiatric disorder</th><th>Comparison</th><th>Change</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="2">SNORA7B</td><td>Nucleus accumbens</td><td>SCZ</td><td>Versus control</td><td>Loss of rhythmicity (day versus night)</td><td>Ketchesin et al. (52)</td></tr><tr><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Downregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORA11C</td><td>Superior temporal sulcus</td><td>ASD</td><td>Versus control</td><td>Upregulation</td><td>Ander et al. (49)</td></tr><tr><td rowspan="3">SNORA13</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>Amygdala, Hippocampus, Prefrontal cortex, Thalamus</td><td>Suicide</td><td>Versus control</td><td>Upregulation</td><td>Glavan et al. (66)</td></tr><tr><td>SNORA14B</td><td>Nucleus accumbens</td><td>SCZ</td><td>Versus control</td><td>Loss of rhythmicity</td><td>Ketchesin et al. (52)</td></tr><tr><td>SNORA21</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td rowspan="2">SNORA22</td><td>Superior temporal sulcus</td><td>ASD</td><td>Old versus young in ASD</td><td>Upregulation</td><td>Stamova et al. (47)</td></tr><tr><td>Primary auditory cortex</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Ander et al. (49)</td></tr><tr><td rowspan="2">SNORA23</td><td>Superior temporal gyrus</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Zhang et al. (51)</td></tr><tr><td>Prefrontal cortex</td><td>Suicide</td><td>Versus control</td><td>Upregulation</td><td>Glavan et al. (66)</td></tr><tr><td rowspan="2">SNORA26</td><td>Superior temporal gyrus</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Zhang et al. (51)</td></tr><tr><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORA27</td><td>Superior temporal sulcus</td><td>ASD</td><td>Versus control</td><td>Upregulation</td><td>Ander et al. (49)</td></tr><tr><td rowspan="2">SNORA28</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>Nucleus accumbens</td><td>SCZ</td><td>Versus control</td><td>Loss of rhythmicity</td><td>Ketchesin et al. (52)</td></tr><tr><td>SNORA40</td><td>Superior temporal gyrus</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Zhang et al. (51)</td></tr><tr><td rowspan="2">SNORA41</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>Superior temporal gyrus</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Zhang et al. (51)</td></tr><tr><td rowspan="2">SNORA46</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>Superior temporal sulcus</td><td>ASD</td><td>Old versus young in ASD</td><td>Upregulation</td><td>Stamova et al. (47)</td></tr><tr><td>SNORA49</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>SNORA51</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORA52</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td rowspan="2">SNORA53</td><td>Superior temporal gyrus</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Zhang et al. (51)</td></tr><tr><td>Dorsolateral prefrontal cortex</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Wright et al. (48)</td></tr><tr><td>SNORA54</td><td>Dorsolateral prefrontal cortex</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Wright et al. (48)</td></tr><tr><td>SNORA57</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Downregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORA59A</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td rowspan="2">SNORA62</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>Amygdala, Hippocampus, Prefrontal cortex, Thalamus</td><td>Suicide</td><td>Versus control</td><td>Upregulation</td><td>Glavan et al. (66)</td></tr><tr><td rowspan="2">SNORA63</td><td>Superior temporal gyrus</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Zhang et al. (51)</td></tr><tr><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORA63B</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORA67</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr></tbody></table>
Role of snoRNAs in Psychiatric Disorders

<table><caption>Table 1. Continued</caption><thead><tr><th>snoRNA</th><th>Sample</th><th>Psychiatric disorder</th><th>Comparison</th><th>Change</th><th>Reference</th></tr></thead><tbody><tr><td>SNORA69</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td></td><td>Lateral habenula</td><td>MDD</td><td>Versus control</td><td>Upregulation</td><td>Lin et al. (64)</td></tr><tr><td>SNORA70F</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>SNORA71D</td><td>STS, PAC</td><td>ASD</td><td>STS versus PAC in ASD</td><td>Downregulation</td><td>Stamova et al. (47)</td></tr><tr><td>SNORA73A</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td></td><td>Superior temporal sulcus</td><td>ASD</td><td>Old versus young in ASD</td><td>Upregulation</td><td>Stamova et al. (47)</td></tr><tr><td>SNORA73B</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Downregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORA74A</td><td>Dorsolateral prefrontal cortex</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Wright et al. (48)</td></tr><tr><td>SNORA74B</td><td>Dorsolateral prefrontal cortex</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Wright et al. (48)</td></tr><tr><td>SNORA74D</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORA76</td><td>Superior temporal gyrus</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Zhang et al. (51)</td></tr><tr><td>SNORD1C</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>SNORD2</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD3A</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>SNORD3B-2</td><td>Frontal cortex<br>Temporal cortex</td><td>Bipolar disorders</td><td>Versus control</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD3C</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td></td><td>Rostral anterior cingulate cortex</td><td>Depressed suicides</td><td>Versus control</td><td>Upregulation</td><td>Zhou et al. 2018</td></tr><tr><td>SNORD5</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Upregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD6</td><td>Superior temporal gyrus</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Zhang et al. (51)</td></tr><tr><td>SNORD7</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD8</td><td>Superior temporal gyrus</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Zhang et al. (51)</td></tr><tr><td></td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Upregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD10</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD12</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Upregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD12C</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>SNORD13</td><td>Superior temporal gyrus</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Zhang et al. (51)</td></tr><tr><td></td><td>Primary auditory cortex</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Ander et al. (49)</td></tr><tr><td>SNORD14E</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>SNORD15A</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>SNORD17</td><td>Dorsolateral prefrontal cortex</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Wright et al. (48)</td></tr><tr><td></td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Downregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD22</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD24</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD25</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Upregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD26</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td></td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Upregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD28</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>SNORD31</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr></tbody></table>
<table><caption>Table 1. Continued</caption><thead><tr><th>snoRNA</th><th>Sample</th><th>Psychiatric disorder</th><th>Comparison</th><th>Change</th><th>Reference</th></tr></thead><tbody><tr><td>SNORD33</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>SNORD34</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Daily use of psychiatric medications</td><td>Positive correlation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD35A</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>SNORD36A</td><td>Dentate gyrus</td><td>MDD</td><td>Versus control</td><td>Upregulation</td><td>Mahajan et al. (63)</td></tr><tr><td>SNORD36B</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD36C</td><td>Dentate gyrus</td><td>MDD</td><td>Versus control</td><td>Upregulation</td><td>Mahajan et al. (63)</td></tr><tr><td>SNORD41</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>SNORD42A</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Downregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD43</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Downregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD44</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>SNORD46</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Downregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td></td><td>Blood</td><td>PTSD</td><td>Versus control</td><td>Downregulation</td><td>Kuan et al. (65)</td></tr><tr><td>SNORD47</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Upregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD49A</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Daily use of psychiatric medications</td><td>Positive correlation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD50A</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>SNORD51</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD54</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td></td><td>Blood</td><td>PTSD</td><td>Versus control</td><td>Downregulation</td><td>Kuan et al. (65)</td></tr><tr><td>SNORD55</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>SNORD57</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td></td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD58A</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td></td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Upregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD59A</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td></td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Upregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD60</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD61</td><td>Dentate gyrus</td><td>MDD</td><td>Versus control</td><td>Downregulation</td><td>Mahajan et al. (63)</td></tr><tr><td>SNORD64</td><td>Superior temporal gyrus</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Zhang et al. (51)</td></tr><tr><td>SNORD65</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD68</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>SNORD69</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD72</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD73A</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Downregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD76</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>SNORD78</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Daily use of psychiatric medications</td><td>Negative correlation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD81</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Upregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD83A</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD85</td><td>Prefrontal cortex synaptosomes</td><td>SCZ</td><td>Versus control</td><td>Downregulation</td><td>Smalheiser et al. (50)</td></tr><tr><td>SNORD88</td><td>STS, PAC</td><td>ASD</td><td>STS versus PAC in ASD</td><td>Upregulation</td><td>Stamova et al. (47)</td></tr><tr><td>SNORD89</td><td>Superior temporal gyrus</td><td>ASD</td><td>Versus control</td><td>Downregulation</td><td>Zhang et al. (51)</td></tr></tbody></table>
Role of snoRNAs in Psychiatric Disorders

<table><caption>Table 1. Continued</caption><thead><tr><th>snoRNA</th><th>Sample</th><th>Psychiatric disorder</th><th>Comparison</th><th>Change</th><th>Reference</th></tr></thead><tbody><tr><td rowspan="2">SNORD90</td><td>Blood</td><td>MDD</td><td>Treatment response</td><td>Upregulation</td><td>Lin et al. (20)</td></tr><tr><td>Brain</td><td>MDD</td><td>With and without treatment</td><td>Upregulation</td><td>Lin et al. (20)</td></tr><tr><td>SNORD95</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td rowspan="2">SNORD101</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Kong et al. (44)</td></tr><tr><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD102</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD110</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Upregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD111B</td><td>Blood</td><td>ASD</td><td>Severe ASD versus mild ASD</td><td>Upregulation</td><td>Salloum-Asfar et al. (45)</td></tr><tr><td>SNORD114-9, 14, 22, 28</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Upregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD114-10</td><td>Amygdala, Hippocampus</td><td>Suicide</td><td>Versus control</td><td>Upregulation</td><td>Glavan et al. (66)</td></tr><tr><td>SNORD114-15</td><td>Amygdala, Hippocampus</td><td>Suicide</td><td>Versus control</td><td>Upregulation</td><td>Glavan et al. (66)</td></tr><tr><td rowspan="2">SNORD114-23</td><td>Dorsolateral prefrontal cortex</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Wright et al. (48)</td></tr><tr><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Upregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD114-26</td><td>Dentate gyrus</td><td>MDD</td><td>Versus control</td><td>Downregulation</td><td>Mahajan et al. (63)</td></tr><tr><td>SNORD114-31</td><td>Amygdala, Hippocampus</td><td>Suicide</td><td>Versus control</td><td>Upregulation</td><td>Glavan et al. (66)</td></tr><tr><td>SNORD115-1</td><td>Nucleus accumbens</td><td>SCZ</td><td>Versus control</td><td>Loss of rhythmicity</td><td>Ketchesin et al. (52)</td></tr><tr><td>SNORD115-5</td><td>Blood</td><td>SCZ</td><td>Versus control (monozygotic twins)</td><td>Hypermethylation</td><td>Melka et al. (54)</td></tr><tr><td>SNORD115-9</td><td>Blood</td><td>SCZ</td><td>Versus control (monozygotic twins)</td><td>Hypermethylation</td><td>Melka et al. (54)</td></tr><tr><td rowspan="2">SNORD115-10</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Upregulation</td><td>Ragan et al. (53)</td></tr><tr><td>Blood</td><td>SCZ</td><td>Versus control (monozygotic twins)</td><td>Hypermethylation</td><td>Melka et al. (54)</td></tr><tr><td>SNORD115-11, 12, 29, 33, 34, 35, 36, 37, 43</td><td>Blood</td><td>SCZ</td><td>Versus control (monozygotic twins)</td><td>Hypermethylation</td><td>Melka et al. (54)</td></tr><tr><td>SNORD115-15, 42</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Upregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD116-3</td><td>Blood</td><td>SCZ</td><td>Versus control (monozygotic twins)</td><td>Hypermethylation</td><td>Melka et al. (54)</td></tr><tr><td>SNORD116-4</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Downregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD116-6</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Daily use of psychiatric medications</td><td>Positive correlation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD116-8, 9, 10, 11</td><td>Blood</td><td>SCZ</td><td>Versus control (monozygotic twins)</td><td>Hypermethylation</td><td>Melka et al. (54)</td></tr><tr><td>SNORD116-27, 29</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Upregulation</td><td>Ragan et al. (53)</td></tr><tr><td>SNORD117</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Daily use of psychiatric medications</td><td>Positive correlation</td><td>Ragan et al. (53)</td></tr><tr><td>snoU2_19</td><td>Anterior cingulate cortex</td><td>SCZ</td><td>Male versus female in SCZ</td><td>Downregulation</td><td>Ragan et al. (53)</td></tr><tr><td>snoU13</td><td>STS, PAC</td><td>ASD</td><td>STS versus PAC in ASD</td><td>Upregulation</td><td>Stamova et al. (47)</td></tr><tr><td>RNU105B</td><td>Blood</td><td>ASD</td><td>Versus control</td><td>Differentially expressed</td><td>Cheng et al. (46)</td></tr></tbody></table>

Details on the samples used, the psychiatric disorder targeted by the study, the type of group compared, and the changes found are presented in the table.

ASD, autism spectrum disorder; MDD, major depressive disorder; PAC, primary auditory cortex; PTSD, posttraumatic stress disorder; SCZ, schizophrenia; STS, superior temporal sulcus.
Major depressive disorder

<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

Autism spectrum disorder

<figure><img src="image_5.png" /></figure>

Splicing alterations correlated with snoRNAs
expression in genes involved in synaptic functions

Schizophrenia

<figure><img src="image_6.png" /></figure>

Loss of snoRNAs enrichment
among the top 100 rhythmic transcripts

SNORA14B SNORA7B
SNORA28 SNORD115-1
SNORA35B SNORD13
SNORA46 SNORD3B-1
SNORA71B SNORD3C
SNORA72 SNORD94

**Figure 2.** Presentation of the main pathophysiological mechanism identified for snoRNAs as related to psychiatric disorders. These mechanisms involve messenger RNA modifications for major depressive disorder and especially response to antidepressant treatment (20), pseudouridine modifications in rRNA in major depressive disorder (64), dysregulation of snoRNA rhythmic expression in schizophrenia (52), and alteration of messenger RNA splicing of genes related to synaptic functions in autism spectrum disorder (51). rRNA, ribosomal RNA; snoRNA, small nucleolar RNA.

mechanistic studies in animal models are warranted to determine the functional significance of altered snoRNA expression. As shown in the article by Lin *et al.* (20), human and animal approaches appear to be complementary to explore the role of snoRNA in psychiatric disorders. Moreover, these approaches should also integrate sex specificity to explore the therapeutic potential of snoRNAs in psychiatric disorders and their potential as biomarkers for sex specificity in mental health conditions.

Furthermore, previous research investigated how snoRNA expression levels differ between species, reflecting phylogenetic relationships. This area of research could be expanded to provide more details on how snoRNAs have evolved to regulate processes across species, leaving a gap in understanding their evolutionary significance and functional diversification.

Moreover, we have chosen to focus on SNORD and SNORA in this review, but within snoRNA, Cajal body-specific RNAs also play a pivotal role in the pseudouridylation and methylation of snRNAs and rRNAs, thereby influencing their function. Therefore, they may play a relevant role in psychiatric disorders and deserve to be investigated.

Finally, evidence suggests that small RNAs can be posttranscriptionally modified in a variety of ways that significantly influence their function across various biological processes (85,86). Among the possible modifications, N-6-methyladenosine (m6A) consists in a methylation modification of the sixth nitrogen (N) atom of adenine (A) (87). It plays a critical role in various biological processes, including meiosis (88,89), circadian rhythm (90), cell differentiation (91), and stress responses (92). Interestingly, snoRNAs were identified as a class of m6A-containing ncRNAs, and over 25% of both classes (SNORA and SNORD) were found to have at least 1 m6A (93). In a subset of human box C/D and C'/D' snoRNA base pair was found to be reversed by placing a C at the usual G position and thereby creating a GAC sequence that potentially targets the A for N6-methylation. Furthermore, research has identified that methylation in snoRNA prevents binding of the 15.5-kDa protein and the induced folding of the RNA, suggesting a regulatory function for this process (94). Nevertheless, research into the significance and biological impact of small RNA modifications in health and disease remains in its

infancy. The study of these modifications may also serve as biomarkers, which could represent a promising avenue for future research (95).

CONCLUSIONS

Studies investigating the pathophysiological mechanisms associated with snoRNA in psychiatric disorders are scarce, although they are warranted. As previously reported for SNORD90, snoRNAs may be valuable biomarkers of treatment response or potential targets for new treatments.

ACKNOWLEDGMENTS AND DISCLOSURES

GT holds a Canada Research Chair (Tier 1) and is supported by grants from the Canadian Institutes of Health Research (Grant Nos. FDN148374, ENP161427 [ERA-NET ERA PerMed], PJT183903, PJT189993) and the National Institutes of Health (Grant No. R56MH131818-01).

The authors report no biomedical financial interests or potential conflicts of interest.

ARTICLE INFORMATION

From the McGill Group for Suicide Studies, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada (JS, GT); and Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey (RL).

Address correspondence to Gustavo Turecki, M.D., Ph.D., at gustavo.turecki@mcgill.ca.

Received Aug 20, 2024; revised Oct 20, 2024; accepted Oct 28, 2024.

Supplementary material cited in this article is available online at https://doi.org/10.1016/j.bpsgos.2024.100415.

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