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Page 14 Donskov et al. J Transl Genet Genom 2021;5:136-62 https://dx.doi.org/10.20517/jtgg.2021.12

Whereas we did not find significant enrichment of NTC genes overall, we found that sex-biased genes are
significantly enriched with NR encoding genes at the prenatal stage, with particular enrichment among sex-
biased genes in the medial frontal cortex (P = 0.006), orbitofrontal cortex (P = 0.004), and striatum (P =
0.010) [Figure 5 and Supplementary Table 12]. In frontal cortical tissues, these include RORB, NR4A2,
NR4A3, and NR3C2, the expression of which are all higher in women than in men. In striatal tissue,
NURR1, NR1D2, NR2F6, and THRB are all sex-differentially expressed with expression being higher in men
- except for NR2F6 that is female-biased. Several NR coregulators are similarly sex-differentially expressed
in these structures in the prenatal stage. At later developmental stages, expression of sex-biased NTC genes
is consistently higher in women compared to men [Figure 5]. Interestingly, NTC genes in SZ GWS loci are
significantly overrepresented among NTC genes that display male-biased expression in the prenatal
striatum (Fisher’s exact test; P = 0.0193) and NTC genes with ASD-associated RCVs among female-biased
genes in the prenatal orbito- and medial frontal cortex (Fisher’s exact test; P = 0.003). The density of PD-
associated NTC genes were furthermore high in the cluster of genes with female-biased cortical expression
in puberty [Figure 5]. Among genes reported to be sex-differentially methylated in the earliest stages of fetal
brain development, only a minor fraction encodes NTC genes [Supplementary Table 5], but particularly SZ
MWAS risk genes clustered among genes with female-biased thalamic dominant expression [Figure 5].

DISCUSSION
Human brain development is a protracted process that begins in the early prenatal stage and extends
[125]
through late adolescence and even adulthood . The process is genetically organized, but it is shaped and
adapted in the context of environmental input. Neither genes nor environmental clues are determinative in
terms of outcome, but disruption to either may affect the maturing brain and mind. The CNS and the
endocrine system work in synergy to sense and act upon endogenous and environmental cues. Whereas the
CNS response is rapid and mostly transient, the endocrine response maintains homeostasis and long-term
control through various molecular mechanisms that include the genomic actions of ligand-activated NRs. In
line with the scientific consensus that the origin of psychopathology is neurodevelopmental, the brain is
most vulnerable to the effect of steroid imbalances and disrupted NR-mediated signaling at the earliest
stages of development [126-129] . Balanced NR-mediated signaling, however, remains important throughout life,
[130]
and steroid levels exhibit a maximum in young men and women (~20 years) but vary greatly in
abundance during periods of hormonal transition (childhood, puberty, post-partum, and menopause), thus
overlapping with the vulnerability periods and age of onset of many PDs. Altered steroidogenic activity and
imbalances in total circulating cholesterol and other lipid metabolites have been reported in a range of
PDs [131,132] . In addition to endogenous steroids and derivatives of retinoids, fatty acids, cholesterol, lipophilic
hormones, and vitamins, NRs further act as sensors for a range of xenobiotics, antibiotics, and synthetic
compounds - with implications for the therapeutic effect of CNS drugs and CNS side effects of non-CNS-
[16]
[133]
targeting drugs . NR-mediated signaling thus constitutes a delicate molecular mechanism that is both
vulnerable to biological dysregulation and interesting as a pharmacological target in the context of mental
health.

Genomic vulnerability to dysregulated nuclear receptor-mediated signaling in mental illness
We found that the genetic NTC risk burden is high across psychiatric diagnostic entities. Particularly, we
found that on average ~15% of SZ, MDD, and BPD GWS loci harbor NTC genes, and the NTC gene set
overall displays significant association to these disorders. In addition, nearly 20% of ASD-associated RCV-
harboring genes are members of the NTC. Although genetic studies have highlighted the implication of
individual NR and NR coregulator-encoding genes in mental illness, this is the first study to demonstrate a
consistently elevated genetic burden in the NTC in PDs. The biological relevance of this overrepresentation
of NTC genes among PD risk genes is further substantiated by the high number of NTC genes that reside in
multi-PD and CD GWS loci and the enrichment of NTC genes among differentially methylated genes in