Genetic variants associated with major depressive disorder (MDD) are enriched in the regulatory genome. Here, we investigate gene-regulatory mechanisms underlying MDD compared to neurotypical controls by combining single-cell chromatin accessibility with gene expression in over 200,000 cells from the dorsolateral prefrontal cortex of 84 individuals. MDD-associated alterations in chromatin accessibility were prominent in deep-layer excitatory neurons characterized by transcription factor (TF) motif accessibility and binding of NR4A2, an activity-dependent TF reactive to stress. The same neurons were enriched for MDD-associated genetic variants, disrupting TF binding sites linked to genes that likely affect synaptic communication. Furthermore, a gray matter microglia cluster exhibited decreased accessibility in individuals with MDD at binding sites bound by TFs known to regulate immune homeostasis. Finally, we identified gene-regulatory effects of MDD-risk variants using sequence-based accessibility predictions, donor-specific genotypes and cell-based assays. These findings shed light on the cell types and regulatory mechanisms through which genetic variation may increase the risk of MDD.
© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.