Genome-wide Association and Multi-omics Studies Identify MGMT As a Novel Risk Gene for Alzheimer's Disease Among Women
Overview
Authors
Affiliations
Introduction: Variants in the tau gene (MAPT) region are associated with breast cancer in women and Alzheimer's disease (AD) among persons lacking apolipoprotein E ε4 (ε4-).
Methods: To identify novel genes associated with tau-related pathology, we conducted two genome-wide association studies (GWAS) for AD, one among 10,340 ε4- women in the Alzheimer's Disease Genetics Consortium (ADGC) and another in 31 members (22 women) of a consanguineous Hutterite kindred.
Results: We identified novel associations of AD with MGMT variants in the ADGC (rs12775171, odds ratio [OR] = 1.4, P = 4.9 × 10) and Hutterite (rs12256016 and rs2803456, OR = 2.0, P = 1.9 × 10) datasets. Multi-omics analyses showed that the most significant and largest number of associations among the single nucleotide polymorphisms (SNPs), DNA-methylated CpGs, MGMT expression, and AD-related neuropathological traits were observed among women. Furthermore, promoter capture Hi-C analyses revealed long-range interactions of the MGMT promoter with MGMT SNPs and CpG sites.
Discussion: These findings suggest that epigenetically regulated MGMT expression is involved in AD pathogenesis, especially in women.
Acharya V, Fan K, Snitz B, Ganguli M, DeKosky S, Lopez O Alzheimers Dement. 2025; 21(3):e14461.
PMID: 40042063 PMC: 11880917. DOI: 10.1002/alz.14461.
Functional insight into East Asian-specific genetic risk loci for Alzheimer's disease.
Cho M, Chaudhuri S, Liu S, Park T, Huang Y, Rosewood T Alzheimers Dement. 2025; 21(2):e14553.
PMID: 39991798 PMC: 11848548. DOI: 10.1002/alz.14553.
Nazarian A, Morado M, Kulminski A Geroscience. 2025; .
PMID: 39751715 DOI: 10.1007/s11357-024-01477-6.
Examination of MGMT as a risk gene for dementia in the Amish.
Main L, Song Y, Lynn A, Laux R, Miskimen K, Osterman M Alzheimers Dement. 2024; 21(1):e14356.
PMID: 39711484 PMC: 11782184. DOI: 10.1002/alz.14356.
Linking Environmental Genotoxins to Neurodegenerative Diseases Through Transcriptional Mutagenesis.
Verheijen B, Vermulst M Int J Mol Sci. 2024; 25(21).
PMID: 39518982 PMC: 11545915. DOI: 10.3390/ijms252111429.