Comprehensive characterization of the RNA editing landscape in the human aging brains with Alzheimer's disease

·We discovered genome-wide landscape of RNA editing signals from 4208 (1364 Alzheimer's disease [AD] cases vs. 742 healthy controls) RNA-seq data across nine human brain regions from three large brain biobanks (Mount Sinai Brain Bank [MSBB], Mayo Clinic [MAYO] Religious Order Study and Memory and Aging Project [ROSMAP]) tied with AD, including in sex-specific and apolipoprotein E4 (APOE4) -specific manner adjusting for age, post mortem interval (PMI), sex, and APOE4 status. ·We emphasize 127 genes, including SYT11, KCNIP4, NRG3, ANKS1B, and RALYL, exhibiting significant RNA editing loci shared by multiple brain tissues, mainly implicated in synaptic plasticity, signaling and transmission, neuronal development, and morphogenesis. ·Brain-wide tissue-specific cis-regulatory variants (cis-edQTLs) were inspected using matched genotyping data from 3627 samples from all brain biobanks. We revealed 147 colocalized AD-GWAS and cis-edQTLs signals pertaining to 48 likely causal genes comprising CLU (rs7982, rs1532278), BIN1 (rs2276582, rs3768863), GRIN3B (rs10417824, rs1058603), NYAP1 (rs12539172), DGKQ (rs4690197, rs3733347), CLPTM1 (rs204468), etc. ·Colocalized signals show affiliations to tau protein binding, amyloid-β regulation, cellular morphogenesis, and immune response pathway suggesting possible roles of epitranscriptomic mechanisms in shaping the AD risk.