Identification of endoplasmic reticulum stress-related genes associated with Alzheimer's disease risk: A multi-omics Mendelian randomization analysis

Nov 28, 2025Journal of affective disorders

Genes linked to cell stress and Alzheimer’s disease risk identified using genetic and molecular data

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Abstract

A total of 245 mQTLs, 29 eQTLs, and 7 pQTLs were identified as associated with Alzheimer's disease risk.

The gene CHRNE showed consistent positive associations in both blood and brain analyses, indicating a potential link to cholinergic dysfunction in Alzheimer's disease.
CHMP1A was associated with Alzheimer's across all three regulatory layers, suggesting that decreased expression may disrupt cellular waste management and increase risk.
Reduced expression of the calcium homeostasis regulators GRINA and ATP2A1 was validated, which may exacerbate endoplasmic reticulum stress-related neuronal injury.
Findings support a multi-omics approach to understanding the genetic factors contributing to Alzheimer's disease risk through endoplasmic reticulum stress.

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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.

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Identification of endoplasmic reticulum stress-related genes associated with Alzheimer's disease risk: A multi-omics Mendelian randomization analysis

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