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

• DOI: 10.1016/j.cell.2023.08.040
• Publication Date: 2023-09-28T14:31:52Z
• Authors: 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
• Keywords: Epigenome; Epigenomics; Gene regulatory network

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 transcriptomic landscapes 850,000 nuclei from prefrontal cortexes 92 individuals with without to build a map the brain regulome, including profiles, regulators, co-accessibility modules, peak-to-gene links in cell-type-specific manner. We develop methods multimodal integration detecting modules using linking. show risk enriched microglial enhancers specific TFs SPI1, ELF2, RUNX1. detect 9,628 ATAC-QTL loci, which integrate alongside prioritize variant circuits. report differential accessibility late glia early neurons. Strikingly, late-stage brains global epigenome dysregulation indicative erosion cell identity loss.