Functional Screening of Alzheimer Pathology Genome-wide Association Signals in Drosophila
Functional Screening of Alzheimer Pathology Genome-wide Association Signals in Drosophila
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DOI：
10.1016/j.ajhg.2011.01.006
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发表时间：
2011-02-11
影响因子：
9.8
通讯作者：
De Jager, Philip L.
中科院分区：
文献类型：
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作者：
Shulman, Joshua M.;Chipendo, Portia;De Jager, Philip L.
我们利用与阿尔茨海默病（AD）相关的果蝇模型，对全基因组扫描发现的与人类AD病理学定量测量相关的基因座进行功能筛选。在评估的15个基因组区域中的6个中，基于与Tau的神经毒性的体内相互作用，我们成功地鉴定了这种关联的因果基因，Tau在AD中形成神经元缠结。在最重要的结果中，SLC2A14中编码葡萄糖转运蛋白的rs10845990显示出与AD病理学相关的复制证据，并且果蝇直系同源物Rs11中功能的获得和丧失分别与Tau毒性的抑制和增强相关。我们的策略耦合全基因组关联在人类与功能筛选的模式生物可能是一个强大的方法，在AD和其他复杂的遗传疾病的基因发现。
We have leveraged a Drosophila model relevant to Alzheimer disease (AD) for functional screening of findings from a genome-wide scan for loci associated with a quantitative measure of AD pathology in humans. In six of the 15 genomic regions evaluated, we successfully identified a causal gene for the association, on the basis of in vivo interactions with the neurotoxicity of Tau, which forms neurofibrillary tangles in AD. Among the top results, rs10845990 within SLC2A14, encoding a glucose transporter, showed evidence of replication for association with AD pathology, and gain and loss of function in glut1, the Drosophila ortholog, was associated with suppression and enhancement of Tau toxicity, respectively. Our strategy of coupling genome-wide association in humans with functional screening in a model organism is likely to be a powerful approach for gene discovery in AD and other complex genetic disorders.