Association of MGMT and BIN1 genes with Alzheimer's disease risk across sex and APOE ε4 status

Le Borgne, Julie, EADB, Amouyel, Philippe, Andreassen, Ole, Frikke‐Schmidt, Ruth, Hiltunen, Mikko, Ingelsson, Martin, Ramirez, Alfredo, Rossi, Giacomina, Ruiz, Agustin, Sanchez‐Juan, Pascual, Sims, Rebecca ORCID: https://orcid.org/0000-0002-3885-1199, Sleegers, Kristel, Tsolaki, Magda, van der Lee, Sven J., Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259, Lambert, Jean‐Charles and Bellenguez, Céline 2024. Association of MGMT and BIN1 genes with Alzheimer's disease risk across sex and APOE ε4 status. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 20 (3) , pp. 2282-2284. 10.1002/alz.13550

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Abstract

Chung et al. reported a novel association of the Alzheimer's disease (AD) risk with genetic variants in the MGMT gene in women.1 The genome-wide significant signals were found in women lacking the apolipoprotein E ε4 allele (APOEε4-) from 30 studies of the Alzheimer's Disease Genetics Consortium (ADGC) (3399 AD cases and 6905 controls), and in a Hutterite cohort (31 members of a consanguineous kindred with different APOEε4 statuses, including 5 AD cases who were all women). The effect sizes reported were large: odds ratio [OR] = 1.44 [1.26–1.64], P = 4.95 × 10-8 in ADGC for rs12775171, and OR = 2.02 [1.80–2.26], P = 1.9 × 10-14 in the Hutterites for rs2803456 and rs12256016. The association found in the ADGC was consistent across studies and not significant in the three other subsets defined by sex and APOEε4 status (women APOEε4+, men APOEε4-, and men APOEε4+) for which effect sizes were not reported. We aimed at replicating the association of MGMT with AD risk in the meta-analysis of 6 case–control studies from the European Alzheimer & Dementia Biobank (EADB) consortium: EADB-core,2 EADI (European Alzheimer's Disease Initiative),3, 4 GERAD (Genetic and Environmental Risk in AD),5 DemGene,6 GR@ACE-DEGESCO,7 and Bonn.2 We considered a total of 33,677 AD cases and 48,158 controls, all of European ancestry, including 10,354 AD cases and 19,910 controls who were female and APOEε4- (Figure 1, Tables S1, and S2 in supporting information). The samples were genotyped with different chips and then imputed using  the TOPMed reference panel2 (supporting information). In each study, we tested the association of MGMT variants with AD in the four subsets defined by sex and APOEε4 status. Analyses were adjusted on principal components, and results were combined across studies in a fixed effect meta-analysis with an inverse-variance weighted approach.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	Wiley
ISSN:	1552-5260
Funders:	Fondation pour la Recherche sur Alzheimer, Research Council of Norway, German Federal Ministry of Education and Research, ISCIII-Ministry of Health Spain, Medical Research Council UK, UKDRI
Date of First Compliant Deposit:	4 December 2023
Date of Acceptance:	11 October 2023
Last Modified:	04 Apr 2024 13:58
URI:	https://orca.cardiff.ac.uk/id/eprint/164499

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