Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer's disease brains.

Journal Article (Journal Article)

BACKGROUND: In the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimer's disease (LOAD) and translate the associations to causation. METHODS: We conducted ATAC-seq profiling using NeuN sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner. RESULTS: We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100 kb of SNP). While the non-neuronal nuclei did not show LOAD-specific differences, stratification by sex identified 842 LOAD-specific chromatin accessibility sites in females. Seven of these sex-dependent sites in the non-neuronal samples overlapped LOAD-GWAS regions including APOE. LOAD loci were functionally validated using single-nuclei RNA-seq datasets. CONCLUSIONS: Using brain sorted-nuclei enabled the identification of sex-dependent cell type-specific LOAD alterations in chromatin structure. These findings enhance the interpretation of LOAD-GWAS discoveries, provide potential pathomechanisms, and suggest novel LOAD-loci.

Full Text

Duke Authors

Cited Authors

  • Barrera, J; Song, L; Gamache, JE; Garrett, ME; Safi, A; Yun, Y; Premasinghe, I; Sprague, D; Chipman, D; Li, J; Fradin, H; Soldano, K; Gordân, R; Ashley-Koch, AE; Crawford, GE; Chiba-Falek, O

Published Date

  • August 24, 2021

Published In

Volume / Issue

  • 16 / 1

Start / End Page

  • 58 -

PubMed ID

  • 34429139

Pubmed Central ID

  • PMC8383438

Electronic International Standard Serial Number (EISSN)

  • 1750-1326

Digital Object Identifier (DOI)

  • 10.1186/s13024-021-00481-0

Language

  • eng

Conference Location

  • England