BACKGROUND: Endoplasmic Reticulum (ER) stress is implicated in Alzheimer's disease (AD) development. This study aims to identify ER stress-related genes associated with AD risk.
METHODS: This study used a multi-omics framework based on Summary-data-based Mendelian Randomization (SMR) to investigate associations between ER stress-related genes and AD. Blood-derived quantitative trait loci (QTL) datasets, including methylation (mQTL), expression (eQTL), and protein (pQTL) data, were integrated with AD genome-wide association study (GWAS) results from FinnGen R12 (discovery) and GCST90027158 (validation). Colocalization and multi-omics integration analyses identified shared variants and regulatory relationships. Brain tissue eQTL data from GTEx were used for validation.
RESULTS: SMR analysis identified 245 mQTLs, 29 eQTLs, and 7 pQTLs associated with AD risk. The Tier 1 gene CHRNE showed consistent positive associations across blood and brain eQTL analyses, implicating cholinergic dysfunction in AD susceptibility. The Tier 2 gene CHMP1A was associated with AD across all three regulatory layers, suggesting that reduced expression of this endosomal sorting and autophagy-related protein may disrupt proteostasis and increase AD risk. The Tier 3 genes GRINA and ATP2A1 were validated across mQTL and eQTL analyses, indicating that reduced expression of these calcium homeostasis regulators may aggravate ER stress-related neuronal injury.
CONCLUSIONS: Our study provides genetic evidence supporting the involvement of ER stress in AD through a multi-omics SMR framework. The findings highlight three major pathogenic pathways underlying AD susceptibility: cholinergic dysfunction mediated by CHRNE, proteostasis imbalance linked to CHMP1A, and calcium signaling disruption driven by GRINA and ATP2A1. These results not only offer new insights into the molecular mechanisms of AD but also identify high-confidence targets for precision therapeutic development focused on ER stress regulation.
