Background: Given the struggle in the field of psychiatry to realize the precise diagnosis and treatment, it is in an urgent need to redefine psychiatric disorders based on objective biomarkers. The results generated from large psychiatric genomic consortia show us some new vantage points to understand the pathophysiology of psychiatric disorders. Nevertheless, how to relate these captured signals to the more refined disease dimensions has yet to be established. Methods: We chose a top-down, cross-disorder approach by using the summary statistics of GWAS from large psychiatric genomic consortia to build a genomic structural equation model (SEM) for SCZ, BD and MDD to detect their common factor (CF), and to map a potential causal core gene for the CF, followed by the transcriptional prediction of the identified causal gene in our sample and the discovery of new biotypes based on the prediction pattern of the causal gene in the brain. We then characterized the biotypes in the context of their demographic features, cognitive functions and neuroimaging traits. Outcomes: A common factor emerged from a well-fitting genomic SEM of SCZ, BD and MDD (loading 0.42, 0.35 and 0.09 for SCZ, BD and MDD, respectively). One genomic region in chromosome 6 was implicated in the genetic make-up of the common factor, with fine-mapping analysis marking ZNF391 as a potential causal core gene (posterior possibility = 0.96). Gene expression inference analysis identified eight brain regions showing different expression levels of ZNF391 between patients and controls, with three biotypes arising from clustering patients based on their expression pattern of ZNF391 in the brain. The three biotypes performed significantly differently in working memory (PDMS\_TC = 0.015, PDMS\_TC\_A = 0.0318, PDMS\_t0D = 0.015) and demonstrated different gray matter volumes in right inferior frontal orbital gyrus (RIFOG) in the same order as working memory (biotype 3 > biotype 2 > biotype 1, PRIFOG = 0.0027). Using ZNF391 as instrumental variable (IV), a partial casual path could be linked from RIFOG to working memory (𝛃RIFOG->DMS_TC0D = 4.95, P = 0.0056; 𝛃 RIFOG->DMS_TC = 2.53, P = 0.059; 𝛃RIFOG->DMS\_TC\_A = 2.57, P = 0.056). Interpretation: The general predisposition to several psychiatric disorders may be influenced by variations of ZNF391 , through its effects on right inferior frontal orbital gyrus and working memory. This illustrates the potential of a trans-diagnostic, top-down approach in understanding the commonality of psychiatric disorders.

Spatial expression pattern of ZNF391 gene in the brains of patients with schizophrenia, bipolar disorders or major depressive disorder identifies new cross-disorder biotypes: A trans-diagnostic, top-down approach