Fig. 4. Analysis of developmental and single-cell RNA-seq data suggest a cell-specific pleiotropic role of NR5A2, SATB2, and PPP3CA in SCZ, CD, and UC and showed that PPP3CA expression was strongest in neurons and enteroendocrine and Paneth-like cells of the ileum, colon, and rectum, indicating a possible link to the GBA.

Visualizations of bulk expression of the candidate genes can be found in Supplementary Fig. 42. a Brain expression data from humans of different ages³⁸ confirm GTeX and BLUEPRINT tissue data and show that NR5A2 is almost absent in brain samples. SATB2 is strongly upregulated in the fetal forebrain in midfetal development. This suggests a developmental function that may predispose to disease when dysregulated. PPP3CA expression is strongest in the forebrain and increases with age. Expression in the liver is given for reference. PC, post conception. Data on expression in the developmental gut³⁹ show that NR5A2 is strongly expressed in the ileum and less so in the colon, whereas SATB2 is more abundant in the colon than in the ileum. This is consistent with the observation that SATB2 is significant for UC but not for CD (Table 2). PPP3CA expression is not evident from bulk RNA-Seq data of intestinal tissue. b NR5A2 is expressed in ileal progenitor, stem cells, and transient amplifying (TA) cells, less strongly in colon and rectum, and not in the brain, consistent with bulk RNA-seq results. SATB2 is strongly expressed in all cell types of the colon and rectum. PPP3CA, despite weak expression in the ileum or colon, is enriched in enteroendocrine and Paneth-like cells of the colon and rectum, supporting a role in immunomodulation. In the brain, PPP3CA is enriched in neurons. Overall, these expression data indicate that separate functions are likely in the gut and brain-based on specific expression patterns. NR5A2 expression was not found in the brain, but literature results make brain-specific function highly likely (Supplementary Note 3). Raw data of this figure can be found in Supplementary Data 17. (exPFC glutamatergic neurons from the PFC, exCA1/3 pyramidal neurons from the Hip CA region, GABA GABAergic interneurons, exDG granule neurons from the Hip dentate gyrus region, ASC astrocytes, NSC neuronal stem cells, MG microglia, ODC oligodendrocytes, OPC oligodendrocyte precursor cells, NSC neuronal stem cells, SMC smooth muscle cells, END endothelial cells).