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Title | Genome-wide association and multi-omics studies identify MGMT as a novel risk gene for Alzheimer's disease among women. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Chung J, Das A, Sun X, Sobreira DR, Leung YYee, Igartua C, Mozaffari S, Chou Y-F, Thiagalingam S, Mez J, Zhang X, Jun GR, Stein TD, Kunkle BW, Martin ER, Pericak-Vance MA, Mayeux R, Haines JL, Schellenberg GD, Nobrega MA, Lunetta KL, Pinto JM, San Wang L-, Ober C, Farrer LA |
Journal | Alzheimers Dement |
Date Published | 06/2022 |
ISSN | 1552-5279 |
Abstract | 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. |
DOI | 10.1002/alz.12719 |
Alternate Journal | Alzheimers Dement |
PubMed ID | 35770850 |
PubMed Central ID | PMC9800643 |
Grant List | U01 AG032984 / AG / NIA NIH HHS / United States U01 AG062602 / AG / NIA NIH HHS / United States R01 AG048927 / AG / NIA NIH HHS / United States RF1 AG057519 / AG / NIA NIH HHS / United States U19 AG068753 / AG / NIA NIH HHS / United States U01 AG058654 / AG / NIA NIH HHS / United States R01 AG062634 / AG / NIA NIH HHS / United States |