# Central amygdala single-nucleus atlas reveals chromatin and gene transcription dynamics in human alcohol use disorder

## TL;DR

This study maps gene and chromatin changes in the central amygdala of people with alcohol use disorder, revealing how inhibitory neurons are affected.

## Contribution

The study provides a detailed multi-omic atlas of the central amygdala in AUD, identifying cell-type-specific gene and chromatin changes.

## Key findings

- Inhibitory neurons show significant gene expression and chromatin changes in alcohol use disorder.
- Differentially expressed genes include GABRA2, GRM8, and NCAM1, with enrichment for AUD risk genes.
- Cell-type-specific regulatory elements and transcription factor footprints were identified, including KLF16 involvement.

## Abstract

Regulation of gene expression is a highly coordinated process in both the healthy and pathological brain with unique patterns across a multitude of cell types. Here we present a multi-omic single nucleus study of ~175,000 nuclei from 50 donors with alcohol use disorder (AUD) and control donors without AUD, profiling cell type specific gene expression and chromatin accessibility in the human central amygdala. We identify all major CNS cell types and neuronal subtypes and find inhibitory neurons are particularly affected by AUD. We find high numbers of differentially expressed genes (DEGs) including GABRA2, GRM8, and NCAM1 and show significant enrichment for AUD risk genes within these DEGs. We identified 51,431 cell type-specific, disease associated candidate cis-regulatory elements including an interneuron-associated set of chromatin loops at the AUD risk gene CALN1. Transcription factor footprinting identified Kruppel-like factors upstream of AUD GWAS genes and DEGs. Finally, we also perform cell type-specific fine mapping for AUD GWAS to prioritize variants within functional genomic elements.

The study used snMultiome-seq to map gene expression and chromatin accessibility in human central amygdala cells from people with and without AUD. Here, the authors show that inhibitory neurons are most affected, with KLF16-driven regulatory changes and AUD-risk variants disrupting gene activity.