Single-nucleus chromatin accessibility profiling identifies cell types and functional variants contributing to major...

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Genetic variants associated with major depressive disorder (MDD) are concentrated in the genome's regulatory regions.
• Understanding the gene-regulatory mechanisms influenced by these variants is crucial for deciphering MDD's complex etiology.

Purpose of the Study:

• To investigate cell-type-specific gene-regulatory mechanisms underlying MDD.
• To identify the role of specific transcription factors and genetic variants in MDD pathogenesis.

Main Methods:

• Combined single-cell chromatin accessibility and gene expression profiling in over 200,000 cells from the dorsolateral prefrontal cortex of 84 individuals.
• Analyzed transcription factor (TF) motif accessibility and binding, particularly NR4A2.
• Utilized sequence-based accessibility predictions, donor-specific genotypes, and cell-based assays to assess MDD-risk variant effects.

Main Results:

• MDD-associated chromatin accessibility changes were prominent in deep-layer excitatory neurons, involving TF binding sites and NR4A2.
• These neurons are enriched for MDD-associated genetic variants that disrupt TF binding sites linked to synaptic communication genes.
• A distinct gray matter microglia cluster showed decreased accessibility in MDD individuals at TF binding sites regulating immune homeostasis.

Conclusions:

• Genetic variations linked to MDD risk influence gene regulation in specific neuronal and immune cell populations within the brain.
• Findings highlight the roles of deep-layer excitatory neurons and microglia in MDD pathophysiology.
• Identified specific regulatory mechanisms, including TF binding disruptions, through which genetic variants may confer MDD risk.