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

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…

• NS
  National Science Foundation

  Award: 1745302
• NI
  National Institutes of Health

  Awards: AG058002, U01AG46152, U01AG61356, P30AG72975, R01AG17917, R01AG15819, P30AG10161