2026 ECNP Congress

PS03-3043

Sex-specific gene expression and genetic predisposition for depression in the EMBER-MDD study

Sophia M. Wissing — T. Lange, L. Steinbach, C. Hohoff, E. Van Assche, B.T. Baune · University of Münster, Department of Psychiatry, Münster, Germany

2026 ECNP Congress

Introduction

Major depressive disorder (MDD) is a multifactorial condition affected by interactions of genetic predisposition, molecular parameters, environmental factors, and psychosocial influences. Overall, women are known to suffer more often from depression, than men. It is likely, that these sex-specific differences are reflected in gene expression and disease susceptibility. Polygenic risk scores (PRS) are a common tool to investigate genetic predisposition for complex disorders, like MDD. Aim of this study was to assess the role of genetic predisposition for depression in sex-specific differences in gene expression in MDD patients.

Methods

The Esketamine Multi-omic Biomarker Evaluation in MDD (EMBER-MDD) is an ongoing, non-interventional study aimed at identifying single- and multi-omic markers for treatment resistance and response in patients with MDD. The present analysis is based on 140 EMBER-MDD patients (MAge= 38; MBMI= 27; 45% female), with continuing data collection. Genomic and transcriptomic data were collected from baseline peripheral whole blood samples using DNA-genotyping (Infinium GSA v3.0+MD arrays, Illumina) and mRNA-sequencing (NovaSeq 6000/X, Illumina). Genomic data were imputed using the 1000 Genomes project and used to calculate MDD-PRS based on MDD summary statistics [1] (significance level=0.001). Transcriptomic data were filtered to remove low-expression genes, resulting in 22,026 genes, and corrected for batch effects. Cell-type composition was estimated using a transcriptome-based deconvolution [2]. Principal components one (PC1) and two (PC2) were calculated to capture main variation. Differentially expressed genes (DEGs) were identified in limma using a linear model adjusted for age, body mass index and cell-type composition (PC1 and PC2). Resulting DEGs were used for enrichment analysis and correlated with MDD-PRS using Spearman’s correlation. Based on MDD-PRS distribution, patients were assigned to low (<20th percentile) and high (>80th percentile) MDD-PRS groups. For each correlated DEG, mean expression per MDD-PRS group was calculated to determine effect size and directionality. All analyses used p<0.05, corrected by FDR (q<0.05) for significance.

Results

We identified 659 significant FDR-corrected DEGs (male vs. female participants), comprising 372 downregulated genes and 287 upregulated genes in males compared to females. Enrichment analysis revealed an upregulation of genes related to immune regulation and response to virus. We identified 29 DEGs correlating significantly with MDD-PRS (none passed FDR correction; q<0.05). Comparison of extreme MDD-PRS groups show a slight-shift towards higher expression in low MDD-PRS group (low MDD-PRS=19 correlated DEGs; high MDD-PRS =10 correlated DEGs).

Conclusions

Our results indicate sex-specific differences in gene expression in MDD patients, particularly affecting the regulation of immune-related pathways. The explorative analysis of the relationship between DEGs and MDD-PRS suggests sex-specific regulation of certain genes in MDD may depend on general genetic predisposition to depression. Individuals with a lower MDD-PRS showed higher expression of sex-specific gene sets enriched for immune-/virus response. This could suggest that a stronger immune/viral response may be linked to lower MDD-PRS. Given the explorative nature of our analysis, this observation should be interpreted cautiously. Overall, the study highlights the value of multi-omic integration (genomic/PRS, transcriptomic, and cell-type composition) in understanding MDD and supports further research into sex-specific molecular mechanisms that may inform targeted treatments.

References

  1. Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. (2025). Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies. Cell, 188(3), 640–652.
  2. Racle, J., Jonge, K. de, Baumgaertner, P., Speiser, D.E., and Gfeller, D. (2017). Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data. eLife Sciences, 6, e26476 (https://elifesciences.org/articles/26476).