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

By Julio A Barrera, Lingyun Song, Alexias Safi, Young Jun Yun, Melanie E. Garrett, Julia E Gamache, Ivana Premasinghe, Daniel Sprague, Danielle Chipman, Jeffrey Li, Hélène Fradin, Karen Soldano, Raluca Gordân, Allison E Ashley-Koch, Gregory E. Crawford, Ornit Chiba-Falek

Posted 09 Apr 2021
bioRxiv DOI: 10.1101/2021.04.07.438835

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. Toward that goal, we conducted ATAC-seq profiling using neuronal nuclear protein (NeuN) sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner. We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions ({+/-}100kb 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. In conclusion, 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. Furthermore, our results convey mechanistic insights into sex differences in LOAD risk and clinicopathology.

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