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Page 20 Donskov et al. J Transl Genet Genom 2021;5:136-62 https://dx.doi.org/10.20517/jtgg.2021.12

thyroid hormones (liothyronine), progesterone receptor antagonist (mifepristone), and bexarotene in
affective disorders and SZ, respectively [177,178] .

Despite their positive effects, but likely owing to their wide applicability, many drugs targeting NRs are
associated with serious adverse effects [169,170] , affecting also the CNS - for instance, suicidal behavior
following administration of the widely prescribed acne-drug Accutane (isotretinoin) . Other NR-targeting
[179]
therapeutic strategies completely fail to demonstrate clinical efficacy, in which cases poor penetration of the
blood-brain barrier seems to be the main impediment. Interestingly, a recently developed fatty acid amide
hydrolase (FAAH)-targeting prodrug strategy appears to successfully facilitate blood-brain barrier diffusion
through masking of small molecule carboxylate-containing NR modulators of therapeutic relevance to CNS
[42]
disorders including ligands for TR, RXR, PPAR, LXR, ER, and RAR .

NRs are extensively expressed throughout the brain, in many tissues and cell types, making them
particularly difficult to target without side effects. In the wake of this realization, accumulating interest has
risen for the targeting of NR coregulators, which tend to be restricted to certain regions and cell types of the
brain. Although commonly viewed as “undruggable” targets due to their large and flexible structures, potent
[180]
small-molecule drugs have been developed to overcome this obstacle . Other drugs target NR coregulators
in an indirect manner through direct interaction with their NR, modulating the interaction between
coregulator and NR, and thus the regulation of target genes [181,182] . We showed that both the NR and NR
coregulator components of the NTC are overrepresented among PD risk genes, supporting the biological
relevance of targeting this group of endogenous coregulators in psychiatry.

Here, we provide a resource for targeting psychiatry-relevant NTC networks with narrow cell specificity and
defined sets of co-expressed interaction partners, which may significantly constrain the burden of off-target
effects, favoring drug precision and safety in NR-based CNS therapeutics.

Perspectives and future research directions
There is an urgent need to identify molecular mechanisms implicated in PDs in order to progress the
development of improved diagnostic tools and personalized medicine in psychiatry. Through mining of
large-scale genomics data, we uncovered an unacknowledged genetic burden in NTC genes and their
downstream genomic targets, supporting dysregulated NR-mediated signaling as a common and core
molecular pathway in PDs. It is thus conceivable that NRs bridge the gap between genetic and
epidemiological risk in mental illness, and that the genetic burden on associated molecular pathways may
direct the individual’s vulnerability to adverse exposures and predict their clinical risk profile. This holds
potential for both drug discovery and options in terms of molecular diagnostics and patient stratification.
NR-mediated signaling has been suggested as a therapeutic target in PDs , but, due to the complexity of
[175]
the NR interaction network, it is challenging to target specific functions of the network while avoiding
serious adverse effects. The mechanisms by which individual cells modulate tissue-specific psychiatry-
relevant NR ligand responsiveness is thus a fundamental issue in targeting NR-mediated signaling in the
brain. Here, we categorized the genetic and epigenetic NTC risk burden in clusters of cell-specific and co-
expressed genes that may provide a useful framework for future CNS NR therapeutic strategies in
psychiatry.

DECLARATIONS
Acknowledgments
We thank the International Genomics of Alzheimer's Project (IGAP) for providing summary results data
for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP