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Page 12 Donskov et al. J Transl Genet Genom 2021;5:136-62 https://dx.doi.org/10.20517/jtgg.2021.12

SMARCD1 (SZ), ARID1B
BCL7A (SZ), NRIP1 (ASD),
(SZ) SMARCC2
(ASD)
3C Progesterone receptor NR3C3 PGR EP300 NCOA1 NCOR2 NCOR2 (cocaine MDD
(CD/SZ/MDD), (ASD) (SZ) dependence),
SRA1 (SZ), NRIP1 TBL1Y (ASD),
(SZ) TBL1Y (ASD)
4A Nerve growth factor 1B NR4A1 NGFI-B EP300 NCOA1
(CD/SZ/MDD) (ASD)
4A Neuron-derived orphan NR4A3 NOR-1 EP300
receptor-1 (CD/SZ/MDD)
4A Nurr-related factor 1 NR4A2 NURR1 MDD
5A Steroidogenic factor-1 NR5A1 SF1 NCOA1
(ASD)
6A Liver receptor homolog-1 NR5A2 LRH1 General cognitive ability, nicotine EP300 NCOA1
dependence (CD/SZ/MDD) (ASD)

NTC: NR transcriptomic complex; ASD: autism spectrum disorder; CD: cross-disorder; SZ: schizophrenia; MDD: major depressive disorder; BPD: bipolar disorder.

Supplementary Table 6 for a list of well-documented interactions), but the biological relevance of these interactions in the brain depends on their co-
expression in the same structures and individual brain cells. Hence, we assessed single cell expression characteristics of NTC genes and identified gene sets that
are specific to individual brain cell types . Overall, 23% of NRs and 13% of NR coregulators are exclusively expressed in specific brain cell types
[95]
[Supplementary Figure 4 and Supplementary Table 8]. For the NRs, these include: PPARA and RORA (astrocytes); NGFIB, PGR, and PPARD (endothelia);
NURR1 and PPARG (microglia); ESR1 and THRB (neurons); and DAX1 (oligodendrocytes).

Next, we clustered NTC genes based on co-expression characteristics in the developing human brain [Figure 4]. This revealed eight distinct larger co-
expression clusters each characterized by peak expression in specific developmental stages or tissues. While the majority of NR encoding genes peak
postnatally (Figure 4 and Supplementary Table 8; Clusters 1-6), a subset (NURR1, NOR-1, NR5A2, TR4, COUP-TF1, COUP-TF2, RORB, THRA, RARA, and

ESR2) peak at the earliest stage of development (Figure 4 and Supplementary Table 8; Cluster 7). Within this group, COUP-TF1 and -2 are particularly
abundantly expressed in the amygdala, while NOR-1 expression peaks in the hippocampus [Figure 4]. Interestingly, the cluster of NTC genes peaking
prenatally hosts the highest density of genes in PD GWS loci and ~80% of RCV harboring NTC genes associated with the early onset PD, ASD. It is also
interesting that a cluster of 23 NTC genes is predominantly expressed in striatal tissue, with a subset displaying very high expression in prenatal striatal tissue.

This striatal-dominant cluster includes the NR encoding genes RARB, RXRG, and SF1, as well as FOXP1 identified in both SZ MWAS and ASD WES (Figure 4
and Supplementary Table 8; Cluster 4). A third cluster with peak expression in the cerebellum houses nine NR encoding genes (ESRRA, NR2F6, RARG, RORC,
RXRB, SHP, ESRRG, RORA, and ESRRB), of which the CD GWS RORA along with ESRRA and ESRRG display particularly high expression in the prenatal