Central amygdala single-nucleus atlas reveals chromatin and gene transcription dynamics in human alcohol use disorder
Abstract
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.
Article Details
Authors (33)
Che Yu Lee
Ahyeon Hwang
Delaney McRiley
Jaywon Lee
Genevieve Thibodeau
Catharine Duman
Xiangyu Zhang
Mario Skarica
Jensine Coudriet
Siwei Xu
Rosemarie Terwilliger
Alexa-Nicole Sliby
Jiawei Wang
Tuan Nguyen
Yujing Liu
Hongyu Li
Yi Dai
Ziheng Duan
Yutong Lei
Yingxin Lin
Jill R. Glausier
David A. Lewis
Joel Gelernter
Paul E. Holtzheimer
Ke Xu
Hang Zhou
Hongyu Zhao
Summer L. Thompson
John H. Krystal
Alicia Che
Jane R. Taylor
Jing Zhang
Matthew J. Girgenti