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Page 2 Donskov et al. J Transl Genet Genom 2021;5:136-62 https://dx.doi.org/10.20517/jtgg.2021.12

Results: We found that NTC genes are significantly overrepresented in genome-, methylome-, and exome-wide
associated loci and that the NTC, as well as NR target gene sets, is overall associated with mental illness.
Accordingly, we identified transcriptomic NTC signatures in patient brain samples. In line with a key role for
orchestrated NR-mediated signaling in the developing brain, particularly NTC co-expression networks with
prenatal peak expression are enriched with differentially methylated, sex-biased, and psychiatry-associated risk
variants.

Conclusion: Here, we provide multilevel evidence that supports genomic NR-mediated signaling as a common and
core molecular mechanism in mental illness, and we highlight specific NR-signaling pathways with putative
diagnostic and pharmacological intervention potential in psychiatry.
Keywords: Nuclear receptor, mental disorders, GWA studies

INTRODUCTION
Psychiatric disorders (PDs) comprise a heterogeneous group of conditions collectively characterized by
changes in patterns of thoughts, emotions, and behaviors. Suggestive of interconnected etiologies, clinical
and therapeutic profiles are overlapping and identified risks are typically non-specifically associated with a
[1-5]
range of mental disorders . Most PDs are highly heritable and thousands of genetic variants are likely to
contribute [6-11] . The effect of genetic risk is further conditional on environmental factors, resulting in
[12]
complex gene-environment interactions (GxE) . Understanding how hereditary risk and environmental
exposures collectively shape the developing brain and mind is thus key to comprehending the pathobiology
of mental illness and the implementation of precision medicine in psychiatry.

Acting at the interface among environmental stimuli, endocrine signaling, and their genomic actions, a
group of ligand-inducible transcription factors, nuclear receptors (NRs), appear uniquely suited to facilitate
GxE in the context of mental health [13,14] . NRs function as biological sensors that respond to a variety of
xenobiotics, steroids, and endogenous lipid- and cholesterol-derived compounds [15,16] . Epidemiological risk
factors involving a steroid or steroid-like response are among the most replicated in psychiatry [17-27] , and
several NR ligands have been associated with PDs (e.g., retinoic acid [28-30] , vitamin D [17,19] ; stress , sex [32-35] ,
[31]
[36]
and thyroid hormones ; endocannabinoids [37,38] ; and polyunsaturated fatty acids [39,40] ). Upon activation, NRs
facilitate fine-tuned transcriptional regulation of defined sets of promotor hormone response element
(HRE)-containing target genes in a cell-, tissue-, and developmental-specific manner. In this way, NRs play
essential roles in the developing and mature central nervous system (CNS) [41,42] and have crucial and diverse
[41]
functions in many aspects of human metabolism, reproduction, inflammation, and physiology .
Consequently, NRs are highly intolerant to loss of function (LoF) mutations , and genetic defects in at
[43]
least 20 of the 48 NRs encoded by the human genome are associated with pathological states, including
neurological disorders and mental illness [41,44] . The latter is highlighted by the severe intellectual disability
displayed by autism spectrum disorder (ASD) and epilepsy cases harboring LoF mutations in genes
encoding retinoic acid receptor-related orphan receptors (RORA and RORB ). Genetic variation in and
[45]
[46]
around a large fraction of NRs has furthermore been associated with PDs and psychiatry-related traits (see
Supplementary Table 1 for a summary). The transcriptional activity and specificity of NRs is ensured
through a dynamic interplay with a comprehensive, but loosely defined, co-regulator complexome,
encompassing > 500 NR coregulators [47,48] - collectively the NR transcriptome complex (NTC). The specific
interactions between individual NRs and their coregulators are in part determined by the biophysical
binding to NR interaction domains (NRIDs) on the regulators . NR coregulators often contain multiple
[49]
NRIDs and display overlap in their specificity and affinity for NRs . In addition, genes may contain several
[49]
different HREs, and NR coregulators may dictate opposite transcriptional outcomes, depending on cellular