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Page 16 Donskov et al. J Transl Genet Genom 2021;5:136-62 https://dx.doi.org/10.20517/jtgg.2021.12

SZ - peak in their expression at the earliest stages of brain development. This may be related to the
differences in onset between affective and non-affective PDs. In this regard, it is interesting to note that
ASD risk NTC genes cluster among genes that display female-biased expression in the prenatal cortex and
male-bias in the prenatal striatum, while non-SZ GWS NTC genes, on the contrary, overlap with genes that
are male-biased in the prenatal cortex and female-biased in the postnatal thalamus and cortex. It is thus
conceivable that differences in baseline NTC gene expression in males and females impact on their
vulnerability to genetic alterations in these gene sets and, consequently, on their sex-biased PD risk profiles.

PD-associated NRs are not restricted to the endocrine receptor subclass of the NR family, but they include
lipid sensors and adopted and true orphan receptors, thus potentially broadly bridging the gap between
genetic and epidemiological risk. In line with this notion, many PD-associated NR coregulators are
ubiquitously expressed in the brain and share a broad range of interactions with PD-associated NRs
[Figure 6 and Table 1]. This includes the bromodomain-containing, epigenetic readers p300, p400, and
BRD8. EP400 is differentially methylated in blood from both ASD and SZ cases and BRD8 is positioned in a
SZ GWS locus. Besides its association to SZ, MDD, and CD, genetic variation in EP300 has also been
[134]
associated with amygdaloid dysfunction in healthy subjects . Altered p300 activity, or the activity of
similar broad-action NR coregulators, may thus widely affect NR-mediated signaling and confer
vulnerability to a spectrum of epidemiological risk associated with a NR-ligand associated molecular
response.

The functional output of signaling through NRs is a change in transcription of gene sets containing
promotor HRE sequences. Whereas we did not find a strong transcriptomic NTC signature in postmortem
brain samples from adult SZ cases, the enrichment of particular HRE sequences in the promotors of DEGs
is in agreement with altered cerebral NR-mediated signaling in SZ. However, it is important to note that
many commonly administered drugs in psychiatry and comorbid disorders will affect CNS NR-mediated
signaling. Hence, it is not possible to ascribe the observed enrichment to a biological disorder or treatment.

At the genomic level, we found that some HRE-containing gene sets are associated with individual PDs,
whereas others display association to PDs in general. This includes the HRE target genes of gonadosteroid
receptors (PGR and ERα) and the retinoic acid receptor (RARβ), which are exclusively associated with
MDD, and RORα HRE targets which have no association to PDs besides ASD. On the other hand, the
retinoic acid receptor X α (RXRα) target genes appear to be more generally associated with mental illness, in
line with the role of RXR heterodimeric complexes .
[120]

Supporting the biological relevance of the observed associations, subsets of HRE gene sets displayed
association to diseases in which NRs are reportedly involved. These include the association of target genes
of the NR1I subfamily of NRs (PXR and CAR that are generally implicated with regulation of energy
metabolism and insulin sensitivity [135,136] ) and the phenotypically interlinked diseases/traits: T2D, HF, and
[137]
[100]
BMI. PPARs have been associated with T2D and AD . Interestingly, the VDRE gene set was
significantly associated with AD and T2D in line with the reported associations between low serum 25-
hydroxyvitamin D levels and AD and T2D , but not with, e.g., ASD and SZ that have been associated with
[138]
early life vitamin D deficiency [17,19] . RXRE was nominally significantly associated with AD, where RXR
agonist administration leads to significant decrease in brain amyloid burden . On the contrary, no
[139]
association was observed between HRE gene sets and COVID-19 (positive vs. population), where NR
biology plays no obvious biological role.