Epigenomic dissection of Alzheimer's disease pinpoints causal variants and reveals epigenome erosion

Xushen Xiong; Benjamin T James; Carles A Boix; Yongjin P Park; Kyriaki Galani; Matheus B Victor; Na Sun; Lei Hou; Li-Lun Ho; Julio Mantero; Aine Ni Scannail; Vishnu Dileep; Weixiu Dong; Hansruedi Mathys; David A Bennett; Li-Huei Tsai; Manolis Kellis

doi:10.1016/j.cell.2023.08.040

Epigenomic dissection of Alzheimer's disease pinpoints causal variants and reveals epigenome erosion

Cell. 2023 Sep 28;186(20):4422-4437.e21. doi: 10.1016/j.cell.2023.08.040.

Authors

Xushen Xiong¹, Benjamin T James², Carles A Boix², Yongjin P Park³, Kyriaki Galani², Matheus B Victor⁴, Na Sun², Lei Hou², Li-Lun Ho², Julio Mantero², Aine Ni Scannail⁴, Vishnu Dileep⁴, Weixiu Dong⁵, Hansruedi Mathys⁶, David A Bennett⁷, Li-Huei Tsai⁸, Manolis Kellis⁹

Affiliations

¹ Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA 02139, USA; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China.
² Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA 02139, USA; The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
³ Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA 02139, USA; The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Pathology and Laboratory Medicine, Department of Statistics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
⁴ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
⁶ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
⁷ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
⁸ The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: lhtsai@mit.edu.
⁹ Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA 02139, USA; The Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA. Electronic address: manoli@mit.edu.

PMID: 37774680
PMCID: PMC10782612 (available on 2024-09-28)
DOI: 10.1016/j.cell.2023.08.040

Abstract

Recent work has identified dozens of non-coding loci for Alzheimer's disease (AD) risk, but their mechanisms and AD transcriptional regulatory circuitry are poorly understood. Here, we profile epigenomic and transcriptomic landscapes of 850,000 nuclei from prefrontal cortexes of 92 individuals with and without AD to build a map of the brain regulome, including epigenomic profiles, transcriptional regulators, co-accessibility modules, and peak-to-gene links in a cell-type-specific manner. We develop methods for multimodal integration and detecting regulatory modules using peak-to-gene linking. We show AD risk loci are enriched in microglial enhancers and for specific TFs including SPI1, ELF2, and RUNX1. We detect 9,628 cell-type-specific ATAC-QTL loci, which we integrate alongside peak-to-gene links to prioritize AD variant regulatory circuits. We report differential accessibility of regulatory modules in late AD in glia and in early AD in neurons. Strikingly, late-stage AD brains show global epigenome dysregulation indicative of epigenome erosion and cell identity loss.

Keywords: ATAC-QTL; Alzheimer’s disease; GWAS; epigenome; epigenome erosion; fine-mapping; multimodal integration; peak-to-gene linking.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alzheimer Disease* / genetics
Alzheimer Disease* / pathology
Brain* / pathology
Epigenome
Epigenomics
Gene Expression Regulation*
Genome-Wide Association Study
Humans

Abstract

Publication types

MeSH terms

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