Alzheimer&Dementia:全基因组和多组学研究发现女性阿尔茨海默病的新风险基因

2022-07-02 MedSci原创 MedSci原创

阿尔茨海默病(AD)是一种进行性神经退行性疾病,是痴呆症最常见的原因。

阿尔茨海默病(AD)是一种进行性神经退行性疾病,是痴呆症最常见的原因。仅在美国,AD影响了580万人。尽管载脂蛋白E(APOE)ε4等位基因是65岁以后发生的AD最确定和最强的遗传风险因素,但只有≈40%的AD病例携带该等位基因,而人口中≈13.7%,这意味着其他基因对该疾病的遗传结构有贡献。

最近对AD的全基因组关联研究(GWAS)进行了荟萃分析,发现与42个新的和33个以前确定的基因位点有全基因组的显著关联,但仍有很大一部分遗传风险没有得到解释。

其中,tau基因(MAPT)区域的变异与女性乳腺癌和缺乏APOEε4者的AD有关。为此,来自麻省总院的学者采用全基因组和多组学研究,旨在确定与tau相关的新基因。

研究人员进行了两项AD的全基因组关联研究(GWAS),一项是在阿尔茨海默病遗传学联盟(ADGC)的10340名ε4-女性中,另一项是在近亲Hutterite家族的31名成员(22名女性)中。

结果显示,在ADGC(rs12775171,几率[OR]=1.4,P=4.9×10-8)和Hutterite(rs12256016和rs2803456,OR=2.0,P=1.9×10-14)数据集中发现了AD与MGMT变体的新关联。多组学分析显示,在女性中观察到单核苷酸多态性(SNPs)、DNA甲基化CpGs、MGMT表达和AD相关的神经病理特征之间最显著和数量最多的关联。

此外,在整个样本中,在女性中,或特别是在ε4的女性中,都与MGMT的表达呈负相关,与神经病理学特征呈正相关。提示,启动子捕获Hi-C分析显示了MGMT启动子与MGMT SNPs和CpG位点的长程相互作用。

这些发现表明,表观遗传调节的MGMT表达参与了AD的发病机制,特别是在女性AD患者中。

 

参考文献:

Genome-wide association and multi-omics studies identify MGMT as a novel risk gene for Alzheimer's disease among women. https://doi.org/10.1002/alz.12719

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    2023-02-14 xuyu
  4. 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  5. 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  6. 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  7. 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    2022-07-02 ms1000001374430865

    受益匪浅

    0

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