Genome-wide association and multi-omics studies identify MGMT as a novel risk gene for Alzheimer's disease among women.

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 × 10-8 ) and Hutterite (rs12256016 and rs2803456, OR = 2.0, P = 1.9 × 10-14 ) 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.

• Authors: Jaeyoon Chung, Anjali Das, Xinyu Sun, Débora R Sobreira, Yuk Yee Leung, Catherine Igartua, Sahar Mozaffari, Yi-Fan Chou, Sam Thiagalingam, Jesse Mez, Xiaoling Zhang, Gyungah R Jun, Thor D Stein, Brian W Kunkle, Eden R Martin, Margaret A Pericak-Vance, Richard Mayeux, Jonathan L Haines, Gerard D Schellenberg, Marcelo A Nobrega, Kathryn L Lunetta, Jayant M Pinto, Li-San Wang, Carole Ober, Lindsay A Farrer
• Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association (Alzheimers Dement) (Jun 30 2022) ISSN: 1552-5279 [Electronic] United States
• PMID: 35770850 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.