Differential Chromatin Architecture and Risk Variants in Deep Layer Excitatory Neurons and Grey Matter Microglia Contribute to Major Depressive Disorder

Abstract

Major depressive disorder (MDD) associated genetic variants reside primarily in the non-coding, regulatory genome. Here we investigate genome-wide regulatory differences and putative gene-regulatory effects of disease risk-variants by examining chromatin accessibility combined with single-cell gene-expression profiles in over 200,000 cells from the dorsolateral prefrontal cortex (DLPFC) of 84 individuals with MDD and neurotypical controls. MDD-associated accessibility alterations were prominent in deep-layer excitatory neurons characterized by transcription factor (TF) motif accessibility and binding of nuclear receptor (NR)4A2, an activity-dependent TF responsive to pathological stress. The same neurons were significantly enriched for MDD-associated genetic variation disrupting cis-regulatory sites and TF binding associated with genes involved in synaptic communication. Furthermore, a grey matter microglial cluster exhibited differentially closed chromatin in MDD affecting binding sites bound by TFs known to regulate immune homeostasis. In summary, our study points to specific cell types and regulatory mechanisms whereby genetic variation may increase predisposition to MDD.

Pervasive neurovascular dysfunction in the ventromedial prefrontal cortex of female depressed suicides with a history of childhood abuse

“…Identification of genes that are potentially regulated by KLF2/4 was performed using a snATACseq dataset previously generated by our group (75). This dataset includes comprehensive profiling of open chromatin across all cell types of the brain, including a vascular cluster.…”

Contrasting genetic predisposition and diagnosis in psychiatric disorders: a multi-omic single-nucleus analysis of the human orbitofrontal cortex

“…These technologies have enabled the creation of single-cell transcriptomic and epigenomic atlases of the human brain, uncovering hundreds of distinct cell types and even thousands of cellular subtypes within millions of cells across different brain regions 32,33 . Such advancements have greatly enhanced our understanding of the cellular specificity of psychiatric disorders, moving from bulk analyses to the more granular single-cell resolution 26,[34][35][36] . Our study aims to explore the molecular landscape of the orbitofrontal cortex in psychiatric disorders, using postmortem samples from patients and controls.…”