Investigating causal relationships between gene expression and major depressive disorder via brain bulk-tissue and...

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder with complex genetic underpinnings. While genome-wide association studies (GWAS) have identified multiple risk loci, pinpointing causal genes within the human brain remains challenging, particularly given the regulatory complexity across different cell types.

We performed summary data-based MR (SMR) and Bayesian colocalization analyses by integrating bulk-tissue eQTL data from 888 individuals with single-cell eQTL datasets from 192 donors representing major brain cell types (excitatory and inhibitory neurons, astrocytes, microglia, oligodendrocytes, OPCs/COPs, endothelial cells, and pericytes). GWAS summary statistics for MDD (170,756 cases and 329,443 controls) were used to assess the causal impact of gene expression. Sensitivity analyses, including the heterogeneity in dependent instruments (HEIDI) test and Steiger filtering, ensured robust inference.

In bulk tissue analyses, five genes (BTN3A2, SLC12A5, AREL1, GMPPB, and ZNF660) emerged as having robust causal evidence for MDD, displaying consistent MR signals and strong colocalization. Cell type-specific analyses revealed additional candidate genes in excitatory neurons (FLOT1, AL450423.1), astrocytes (AL121821.1), and oligodendrocytes (YLPM1, COP1).

Our integrative approach reveals that causal gene expression profiles differ markedly between bulk-tissue and specific brain cell types, emphasizing cellular heterogeneity in MDD pathogenesis and informing precision therapeutic strategies. These findings underscore the necessity of considering cell type-specific gene regulation when developing therapeutic interventions for MDD.