Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family
Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family
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DOI：
10.1073/pnas.0403535101
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发表时间：
2004-11-02
影响因子：
11.1
通讯作者：
Grupe, A
中科院分区：
文献类型：
--
作者：
Li, Y;Nowotny, P;Grupe, A
虽然早发型常染色体显性形式的阿尔茨海默病（AD）的发展涉及几个基因，但晚发型AD（LOAD）的遗传学是复杂的。几条染色体上的基因位点与该疾病有关，但迄今为止只有载脂蛋白E基因一直被证明是一个危险因素。我们进行了一项大规模的基于单核苷酸多态性（SNP）的关联研究，跨越12号染色体上的连锁区域，在多个病例对照系列中，共计1,089名LOAD患者和1,196名对照受试者，并报告了与甘油醛-3-磷酸脱氢酶（GAPD）基因中SNP的关联。随后对其他染色体上的GAPD旁系同源物的分析表明与其他两个旁系同源物相关。在所有三个样本集中观察到LOAD和三个GAPD基因的复合基因型之间的显著关联。个别而言，这些SNPs在每个病例对照系列中对疾病风险的贡献不同，这表明功能相似基因的变异可能导致疾病风险的系列间异质性。我们的观察结果提出了GAPD基因是AD危险因素的可能性，这一假设与GAPD在神经元凋亡中的作用一致。
Although several genes have been implicated in the development of the early-onset autosomal dominant form of Alzheimer's disease (AD), the genetics of late-onset AD (LOAD) is complex. Loci on several chromosomes have been linked to the disease, but so far only the apolipoprotein E gene has been consistently shown to be a risk factor. We have performed a large-scale single-nucleotide polymorphism (SNP)-based association study, across the region of linkage on chromosome 12, in multiple case-control series totaling 1,089 LOAD patients and 1,196 control subjects and report association with SNPs in the glyceraldehyde-3-phosphate dehydrogenase (GAPD) gene. Subsequent analysis of GAPD paralogs on other chromosomes demonstrated association with two other paralogs. A significant association between LOAD and a compound genotype of the three GAPD genes was observed in all three sample sets. Individually, these SNPs make differential contributions to disease risk in each of the case-control series, suggesting that variants in functionally similar genes may account for series-to-series heterogeneity of disease risk. Our observations raise the possibility that GAPD genes are AD risk factors, a hypothesis that is consistent with the role of GAPD in neuronal apoptosis.