Journal Article Ppublish
PubMed: 40631452 DOI: 10.1002/alz.70452
Comprehensive characterization of the RNA editing landscape in the human aging brains with Alzheimer's disease.
Alzheimers Dement 21(7):e70452
Authors: Amit Kumar Gupta, William Martin, Andrew A Pieper, Yinsheng Wang, Andrew J Saykin, Feixiong Cheng
Affiliations
- Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
- Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
- Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio, USA.
- Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
- Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, USA.
- Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
- Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA.
- Department of Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA.
- Department of Chemistry, University of California, Riverside, California, USA.
- Environmental Toxicology Graduate Program, University of California, Riverside, California, USA.
- Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, Indiana, USA.
- Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
- Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA.
Abstract
INTRODUCTION
While RNA editing has been linked to Alzheimer's disease (AD), its specific impact on the transcriptomic landscape in human AD brains remains under explored.
METHODS
We conducted a comprehensive analysis of RNA editing across nine human brain regions affected by AD, utilizing RNA-seq data and matched whole-genome sequencing data from three human brain biobanks, adjusting for age, post mortem interval, sex, and apolipoprotein E4 (APOE4) status.
RESULTS
RNA-editing events were identified in both AD and healthy control aging brains, highlighting 127 genes with significant RNA editing loci. AD exhibited elevated RNA editing in the parahippocampal gyrus and cerebellar cortex. We also discovered 147 colocalized genome-wide association studies (GWAS) and cis-edQTL (± 1 MB) signals in 48 likely causal genes encompassing CLU, BIN1, and GRIN3B, primarily allied to amyloid and tau pathology, and neuroinflammation.
DISCUSSION
Our findings delineate RNA editing regulatory signatures in human AD, providing novel insights into AD pathophysiology and potential biomarkers and therapeutic targets.
HIGHLIGHTS
·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.
MeSH
Apolipoprotein E4, Genes, Dementia, Alzheimer Disease, Aging, Brain, Genome, Rna Editing, Biomarkers, Sex, Amyloid, Tissues, Morphogenesis, Apolipoproteins