Main Leighanne R, Song Yeunjoo E, Lynn Audrey, Laux Renee A, Miskimen Kristy L, Osterman Michael D, Cuccaro Michael L, Ogrocki Paula K, Lerner Alan J, Vance Jeffery M, Fuzzell M Denise, Fuzzell Sarada L, Hochstetler Sherri D, Dorfsman Daniel A, Caywood Laura J, Prough Michael B, Adams Larry D, Clouse Jason E, Herington Sharlene D, Scott William K, Pericak-Vance Margaret A, Haines Jonathan L
Departments of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Alzheimers Dement. 2025 Jan;21(1):e14356. doi: 10.1002/alz.14356. Epub 2024 Dec 23.
Recently, the O-6-methylguanine-DNA methyltransferase (MGMT) locus was proposed as influencing the risk of Alzheimer's disease (AD) in women who did not carry the apolipoprotein E ε4 allele. We examined an Amish founder population for any influence of genetic variation in and around the MGMT locus on the risk for dementia.
Genetic association was performed for single nucleotide polymorphisms (SNPs) surrounding the MGMT locus. A total of 946 individuals of Amish descent between the ages of 76 and 95 who were classified as cognitively impaired or cognitively unimpaired were included. Multiple statistical models were applied to test for replication.
The results for the previously associated individual SNPs were not significant. However, a different SNP (rs7909468) generated significant results under a model different from the previous report.
The MGMT locus may influence the risk of AD, although its genetic mechanisms remain unclear and warrant further study.
Association analyses around the O-6-methylguanine-DNA methyltransferase (MGMT) locus showed a study-significant single nucleotide polymorphism (SNP), rs7909468, in a female cognitively impaired group lacking the apolipoprotein E ε4 genotype. Functional implications of rs7909468 are relatively unexplored, but in silico analyses indicate it may regulate MGMT expression. rs7909468 was not in linkage disequilibrium with other SNPs found to be significant in this region and appears as a distinct novel association.
最近，有人提出O-6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）基因座会影响未携带载脂蛋白Eε4等位基因的女性患阿尔茨海默病（AD）的风险。我们在一个阿米什人创始人群体中研究了MGMT基因座及其周围的基因变异对痴呆症风险的影响。
对MGMT基因座周围的单核苷酸多态性（SNP）进行基因关联分析。纳入了946名年龄在76至95岁之间的阿米什后裔个体，他们被分类为认知受损或认知未受损。应用多种统计模型进行重复检验。
先前相关的单个SNP的结果不显著。然而，一个不同的SNP（rs7909468）在一个与先前报告不同的模型下产生了显著结果。
MGMT基因座可能影响AD的风险，尽管其遗传机制仍不清楚，值得进一步研究。
围绕O-6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）基因座的关联分析显示，在一个缺乏载脂蛋白Eε4基因型的女性认知受损组中，一个单核苷酸多态性（SNP）rs7909468具有研究显著性。rs7909468的功能意义相对未被探索，但计算机分析表明它可能调节MGMT的表达。rs7909468与该区域其他显著的SNP不存在连锁不平衡，似乎是一种独特的新型关联。
