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Page 18 Donskov et al. J Transl Genet Genom 2021;5:136-62 https://dx.doi.org/10.20517/jtgg.2021.12

and adulthood. However, ERα and PGR both display a link to MDD, as their target ESRE and PGRE gene
sets are both associated with MDD [Figure 6]. DEGs identified in SZ postmortem brains are further
enriched with PGRE in their promotor sequences. All gonadosteroid receptors share a range of NR
coregulators, but both ESR1 and PGR show cell-specific expression (neurons and endothelia, respectively)
and have potential receptor-specific NR coregulators from within their co-expression clusters. For ERα, this
includes SZ GWS PRMT8, although their biophysical interaction remains to be systematically examined.

Corticosteroid receptors
Exposure to traumatic, maternal, and early life stress is a major risk factor in many PDs, including SZ, BPD,
MDD, and anxiety disorders [26,145,146] . Among the NTC genes that harbor ASD-associated RCVs is NR3C2
encoding the mineralocorticoid receptor (MR). MR is a high-affinity corticosteroid receptor that acts in
synergy with the glucocorticoid receptor (GR) to mediate the molecular stress response. Both GR and MR
belong to a gene co-expression cluster with peak expression in puberty and adulthood; however, whereas
GR is widely expressed in the brain and peak in cerebellar tissue, MR expression peaks in limbic tissues, in
accordance with previously published reports . MR plays a well-documented and sex-biased role in stress
[147]
[148]
resilience and depression , where a functional MR haplotype protects against depression following early
life trauma . Unlike MRE target genes, the GRE gene set showed a significant association to MDD
[149]
[Figure 6]. This is in line with a recent study that demonstrated that genetic differences in the immediate
transcriptome response to stress predict the risk of several PDs .
[18]
Retinoid binding nuclear receptor
Retinoids play a crucial role in developmental pathways, but they are also essential to a number of postnatal
processes, including synaptic plasticity . Retinoid signaling is mediated through binding to RARs and
[28]
PPARs in heterodimeric partnership with RXR. Low maternal retinol is a risk factor in SZ in adult offspring
29, and membrane levels of several PUFAs, which signal through the same receptors [150,151] , have been
associated with psychotic, depressive, and manic symptoms in individuals at ultrahigh risk for psychosis .
[39]
Accumulating evidence has implicated retinoid signaling in the pathoetiology of particularly SZ (recently
reviewed by Reay et al. ), and PPAR/RXR and RAR/RXR complexes have been proposed as therapeutic
[28]
[152]
strategies in CNS disorders . Among the RXRs, none have been found in PD GWS loci; however, we
found that the RXRE target gene set of RXRα is significantly associated with CD. Whereas RXR-encoding
genes are not restricted to specific cell types, their heterodimeric partners, PPARs, are. PPARγ is specific to
microglia, PPARα to astrocytes, and PPARδ to endothelia among brain cells - and both PPARA and PPARG
are co-expressed with PD-associated coregulators in these specific cells. While none of the three receptors
have been associated with PDs in GWASs, PPARA and PPARD are differentially methylated in blood from,
respectively, SZ and MDD patients. In addition, we found that the PPARE target gene set of PPARγ is
significantly associated with ASD. It is further noteworthy that both PPARα and -γ can bind and respond to
cannabinoids , thus providing a potential genetic link to the risks and phenotypes associated with
[153]
cannabis use in PDs .
[154]
Among the RAR encoding genes, only RARG resides in a PD GWS locus (SZ), whereas we found that the
RARE target gene set of RARβ is associated with MDD. RARB and RARG have different expression profiles,
and, whereas RARG clusters with genes with peak expression in the cerebellum, RARB expression peaks in
striatal tissue. RARβ and RARγ share a number of NR coregulator interaction partners genetically associated
with PDs [Figure 6].