Identification of Candidate DNA Methylation Biomarkers Related to Alzheimer’s Disease Risk by Integrating Genome and Blood Methylome Data

Authors

Yanfa Sun
Jingjing Zhu
Yaohua Yang
Zichen Zhang
Hua Zhong
Guanghua Zeng
Dan Zhou
Richard S Nowakowski
Jirong Long
Chong Wu
Lang Wu

Publication Date

12-13-2023

Journal

Translational Psychiatry

Abstract

Alzheimer disease (AD) is a common neurodegenerative disease with a late onset. It is critical to identify novel blood-based DNA methylation biomarkers to better understand the extent of the molecular pathways affected in AD. Two sets of blood DNA methylation genetic prediction models developed using different reference panels and modelling strategies were leveraged to evaluate associations of genetically predicted DNA methylation levels with AD risk in 111,326 (46,828 proxy) cases and 677,663 controls. A total of 1,168 cytosine-phosphate-guanine (CpG) sites showed a significant association with AD risk at a false discovery rate (FDR) < 0.05. Methylation levels of 196 CpG sites were correlated with expression levels of 130 adjacent genes in blood. Overall, 52 CpG sites of 32 genes showed consistent association directions for the methylation-gene expression-AD risk, including nine genes (CNIH4, THUMPD3, SERPINB9, MTUS1, CISD1, FRAT2, CCDC88B, FES, and SSH2) firstly reported as AD risk genes. Nine of 32 genes were enriched in dementia and AD disease categories (P values ranged from 1.85 × 10-4 to 7.46 × 10-6), and 19 genes in a neurological disease network (score = 54) were also observed. Our findings improve the understanding of genetics and etiology for AD.

Keywords

Humans, DNA Methylation, Alzheimer Disease, Epigenome, Neurodegenerative Diseases, Biomarkers, CpG Islands, Tumor Suppressor Proteins, Receptors, Cytoplasmic and Nuclear

DOI

10.1038/s41398-023-02695-w

PMID

38092781

PMCID

PMC10719322

PubMedCentral® Posted Date

12-13-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes