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Donskov et al. J Transl Genet Genom 2021;5:136-62 https://dx.doi.org/10.20517/jtgg.2021.12 Page 19

RORs
Patients with pathogenic variations in retinoic acid receptor-related orphan receptors (RORs) present with
ASD as well as seizures. Both RORs (RORα and RORβ) are located in PD GWS loci. The RORB gene is
associated with SZ and further harbors ASD-associated RCVs. RORB is specifically expressed in astrocytes
and resides in a gene co-expression cluster that peaks during prenatal brain development. Besides RORB,
none of the NTC genes with prenatal peaks are astrocyte specific, but single cell genomics in ASD cortical
tissue have associated altered glial RORB expression with ASD . Further supporting the involvement of
[155]
ROR-mediated signaling in ASD, RORα resides in a CD GWS locus and its RORE-containing target genes
are significantly associated with ASD [Figure 6]. This is in agreement with reported ASD risk genes under
[156]
RORα transcriptional regulation . Similarly, an association has been found between ASD and the
significantly overlapping HRE-containing target genes of NRID1 (Rev-ErbA-Alpha) that reportedly acts as a
[157]
repressor of RORE gene sets . Reduced RORA transcript and/or protein levels has been reported in both
blood and postmortem brain tissue from ASD cases . RORs are involved in a number of psychiatry-
[158]
relevant pathways including neurogenesis, stress response, and modulation of circadian rhythms . RORα
[159]
binds with high affinity to the brain-specific cholesterol-metabolite, 24S-hydroxysterol (cerebrosterol),
which has been found differentially abundant in plasma and suggested as a biomarker in ASD .
[160]
Orphan receptors
Located in an MDD GWS locus, NURR1 is specifically expressed in microglia and co-expressed with the SZ
GWS NR coregulators, CNOT1 and GMEB1. However, the biophysical interaction of these coregulators
with NURR1 has not been systematically examined. Although classified as an orphan receptor, NURR1
activity can be modulated by several small molecules [including docosahexaenoic acid (DHA) and other
[162]
unsaturated fatty acids] , as well as non-steroidal anti-inflammatory drugs . NURR1 has been
[161]
characterized as a neuroprotective and anti-inflammatory transcription factor and suggested as a
[163]
[164]
therapeutic target in Parkinson’s disease . The monomer NBRE targets of NURR1 are not significantly
associated with any PD, but, as NURR1 can bind DNA as a heterodimer with RXRs, it has the potential to
modulate CD-associated RXRE target genes.
Little is reported about a role for the DAX1 receptor in mental illness. It is an orphan receptor and has been
reported to act as a repressor of other NRs through heterodimeric interactions with, e.g., MR and GR [165,166] .
However, in the brain, DAX1 is specifically expressed in oligodendrocytes. We found that the HRE half-site
targets of DAX1 display significant association with SZ and interact with several PD-associated NR
coregulators [Figure 6].

Therapeutic potential of targeting nuclear receptor biology in psychiatry
The activity of NRs can be pharmacologically modulated by specific ligands, thereby allowing for agonism,
partial agonism, and antagonism. This has made them primary therapeutic targets for decades , and
[167]
approximately 16% of FDA approved drugs target NRs . A wide spectrum of somatic disorders has
[168]
successfully been targeted by drugs directed at NRs. PPARγ-targeting thiazolidinediones are used in the
[169]
treatment of diabetes, cardiovascular disease, and cancer ; selective ER modulators in ER-positive and
[170]
metastatic breast cancer ; and RXR/RAR-targeting isotretinoin against acne. Furthermore, the well-
known drug bexarotene, a selective RXR agonist, has been effectively used in the treatment of cutaneous T-
cell lymphoma. A range of NR-targeting drugs have also proven efficient in non-psychiatric traits of the
CNS, although most have yet to demonstrate clinical efficacy and sustainability in phase III trials. Whereas
NR modulators are increasingly recognized as potentially powerful therapeutics for neurodegenerative CNS
diseases [104,171-174] , a similar shift in focus remains to be seen for drug discovery programs in PDs. NRs have
[175]
been suggested as therapeutic targets in PDs , and pharmacological targeting of NR-mediated signaling
has demonstrated clinical efficacy in the treatment of PDs , as assessed following administration of
[176]