Integrative SMR prioritizes oxidative stress-related regulatory genes for Alzheimer's disease with brain-tissue validation - PubMed
5 hours ago
- #Alzheimer's disease
- #Mendelian randomization
- #Oxidative stress
- Integrative SMR prioritizes oxidative stress-related regulatory genes for Alzheimer's disease (AD).
- Oxidative stress (OS) plays a critical role in AD pathogenesis, with unclear genetic and epigenetic regulatory mechanisms.
- A three-step summary-based Mendelian randomization (SMR) framework was used, integrating AD GWAS summary statistics with eQTL and mQTL datasets.
- Brain-tissue relevance was evaluated using GTEx v8 and AMP-AD resources.
- Prioritized OS-related candidate genes include CRLS1, PRKAA1, CYP2E1, GPX1, and APP.
- Brain-tissue analyses highlighted KEAP1, SIRT1, and PRDX5 as region-relevant signals.
- Functional enrichment analyses identified critical pathways like 'Nrf2-mediated antioxidant response' and 'PI3K-AKT signaling'.
- Novel regulatory mechanisms were uncovered at methylation sites, linking epigenetic regulation to transcriptional mechanisms.
- The study provides new insights into AD molecular underpinnings and identifies potential therapeutic targets.