2026 ECNP Congress

PS02-2214

Functional genomics to identify the transdiagnostic biosignatures underlying treatment resistance across major psychiatric disorders in the Psych-STRATA consortium

Chiara Possidente — G. Dolgalev, J. Kraft, I. Willcocks, L. Jonsson, B.T. Baune, A. Serretti, M. Ziller, C. Fabbri · University of Bologna, Department of Biomedical an Neuromotor Sciences, Bologna, Italy

2026 ECNP Congress

BACKGROUND

Schizophrenia, bipolar disorder (BD) and major depressive disorder (MDD) are leading causes of disability worldwide. Approximately one in three patients with these conditions does not respond to multiple pharmacological therapies, developing treatment resistance (TR). TR worsens the course of illness, resulting in heightened chronicity and suicidality, and deteriorated functioning and physical health. Given the overlapping genetic architecture across schizophrenia, BD, and MDD [1], TR may reflect shared multi-omic mechanisms, including gene expression and protein levels.

AIM

Using transcriptome- and proteome-wide association studies (TWAS/PWAS), we studied gene and protein expression alterations across samples of TR schizophrenia, BD, and MDD, aiming to identify transdiagnostic biological underpinnings of TR and biomarkers for early detection of patients at risk of developing TR, and to inform novel treatment strategies.

METHODS

We used quality-controlled genome-wide summary statistics for TR in schizophrenia, BD, and MDD, derived from meta-analyses of large European-ancestry cohorts conducted by the Psych-STRATA consortium (N cases-controls: 9,964-19,084 for BD, 32,142-177,428 for MDD, 19,261-21,303 for schizophrenia). For each disorder, TWAS was conducted using S-PrediXcan with a selection of gene expression and splicing reference panels from multiple brain regions (PsychENCODE and GTEx) and other potentially relevant tissues (e.g., blood and thyroid; GTEx) [2,3]. For the PWAS, we employed FUSION, using two protein reference panels from dorsolateral prefrontal cortex (DLPFC) (ROSMAP/Banner) and one plasma panel (UKB-PPP). Gene- and protein-level associations were considered significant at a False Discovery Rate (FDR) < 0.05.

RESULTS

Across disorders, the number of unique features tested ranged from 21,795 to 21,806 for gene expression TWAS, from 15,192 to 15,205 for splicing TWAS, and from 4,606 to 4,663 for PWAS. No significant associations were identified in the TWAS for schizophrenia or BD, in either gene expression or splicing analyses. For MDD, DIP2B gene expression was significantly associated with TR in DLPFC (PsychENCODE; z-score = 4.82, FDR = 0.02) and hippocampus (GTEx; z-score = 4.81, FDR = 0.02). TWF2 and NDUFS8 splicing were significant in spinal cord-C1 (GTEx; z-score = −4.77, FDR = 0.05) and whole blood (GTEx; z-score = 4.74, FDR = 0.05), respectively. No significant associations were identified in the PWAS for any disorder. However, GPR56 (ROSMAP) showed a trend toward significance in schizophrenia (FDR = 0.06). Notably, DIP2B also showed a suggestive signal at the protein level in MDD (FDR = 0.19).

CONCLUSIONS

Although the number of significant signals was limited, they appear to converge on similar neurobiological pathways. DIP2B, with the strongest evidence in MDD, has been implicated in neurodevelopmental disorders and synaptic plasticity. Similarly, TWF2 has been implicated in actin-dependent neuronal morphology and dendritic remodelling. GPR56, involved in cortical development and myelination, has been linked to antidepressant response [4], lending plausibility to its suggestive PWAS signal in schizophrenia, consistent with the hypothesis of shared biological mechanisms underlying TR. Despite using the largest summary statistics for TR currently available, power was still limited by the relatively low number of TR cases. Ongoing analyses will further explore transdiagnostic mechanisms and potential biomarkers for TR across schizophrenia, BD, and MDD.

References

  1. Cross-Disorder Group of the Psychiatric Genomics Consortium. Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders. Cell 2019;179:1469-1482.e11. https://doi.org/10.1016/j.cell.2019.11.020.
  2. Gusev A, Mancuso N, Won H, Kousi M, Finucane HK, Reshef Y, Song L, Safi A; Schizophrenia Working Group of the Psychiatric Genomics Consortium; McCarroll S, Neale BM, Ophoff RA, O’Donovan MC, Crawford GE, Geschwind DH, Katsanis N, Sullivan PF, Pasaniuc B, Price AL. Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat Genet. 2018 Apr;50(4):538-548. https://doi.org/10.1038/s41588-018-0092-1.
  3. Monteiro-Martins S, Sterenborg RBTM, Borisov O, Scherer N, Cheng Y, Medici M, Köttgen A, Teumer A. New insights into the hypothalamic-pituitary-thyroid axis: a transcriptome- and proteome-wide association study. Eur Thyroid J. 2024 Jun 20;13(3):e240067. https://doi.org/10.1530/ETJ-24-0067.
  4. Belzeaux R, Gorgievski V, Fiori LM, Lopez JP, Grenier J, Lin R, Nagy C, Ibrahim EC, Gascon E, Courtet P, Richard-Devantoy S, Berlim M, Chachamovich E, Théroux JF, Dumas S, Giros B, Rotzinger S, Soares CN, Foster JA, Mechawar N, Tall GG, Tzavara ET, Kennedy SH, Turecki G. GPR56/ADGRG1 is associated with response to antidepressant treatment. Nat Commun 11, 1635 (2020). https://doi.org/10.1038/s41467-020-15423-5