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American journal of human genetics. 2025 Apr 7:S0002-9297(25)00111-9. doi: 10.1016/j.ajhg.2025.03.012 Q18.12024

Computational and functional prioritization identifies genes that rescue behavior and reduce tau protein in fly and human cell models of Alzheimer disease

计算和功能优先级确定可救治行为并减少tau蛋白的基因：果蝇模型和人类细胞模型阿尔茨海默病的研究 翻译改进

Morgan C Stephens  1, Jiayang Li  1, Megan Mair  1, Justin Moore  1, Katy Zhu  1, Akash Tarkunde  1, Bismark Amoh  1, Alma M Perez  1, Arya Bhakare  1, Fangfei Guo  1, Joshua M Shulman  2, Ismael Al-Ramahi  3, Juan Botas  4

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作者单位

  • 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA.
  • 2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Center for Alzheimer's and Neurodegenerative Disease, Baylor College of Medicine, Houston, TX 77030, USA.
  • 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA; Center for Alzheimer's and Neurodegenerative Disease, Baylor College of Medicine, Houston, TX 77030, USA.
  • 4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA; Center for Alzheimer's and Neurodegenerative Disease, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: jbotas@bcm.edu.

    • DOI: 10.1016/j.ajhg.2025.03.012 PMID: 40215969

    摘要 中英对照阅读

    Genome-wide association studies (GWASs) in Alzheimer disease (AD) have uncovered over 70 loci significantly associated with AD risk, but identifying the true causal gene(s) at these loci requires systematic functional validation that is rarely performed due to limitations of time and cost. Here, we integrate transcriptome-wide association study (TWAS) with colocalization analysis, fine-mapping, and additional annotation of AD GWAS variants to identify 123 genes at known and suggestive AD risk loci. A comparison with human AD brain transcriptome data confirmed that many of these candidate genes are dysregulated in human AD and correlate with neuropathology. We then tested all available orthologs in two well-established Drosophila AD models that express either wild-type tau or secreted β-amyloid (β42). Experimental perturbation of the 60 available candidates pinpointed 46 that modulated neuronal dysfunction in one or both fly models. The effects of 18 of these genes were concordant with the TWAS prediction, such that the direction of misexpression predicted to increase AD risk in humans exacerbated behavioral impairments in the AD fly models. Reversing the aberrant down- or upregulation of 11 of these genes (MTCH2, ELL, TAP2, HDC, DMWD, MYCL, SLC4A9, ABCA7, CSTF1, PTK2B, and CD2AP) proved neuroprotective in vivo. We further studied MTCH2 and found that it regulates steady-state tau protein levels in the Drosophila brain and reduces tau accumulation in human neural progenitor cells. This systematic, integrative approach effectively prioritizes genes at GWAS loci and reveals promising AD-relevant candidates for further investigation as risk factors or targets for therapeutic intervention.

    Keywords: Alzheimer disease; MTCH2; SPI1; TWAS; behavioral screen; longitudinal transcriptomics; neuroprotective.

    Keywords：computational prioritization; alzheimer disease; tau protein

    全基因组关联研究（GWAS）在阿尔茨海默病（AD）中已经发现了超过70个与AD风险显著相关的位点，但要识别这些位点上的真正因果基因通常由于时间和成本的限制而很少进行系统的功能验证。在这里，我们整合了转录组范围内的关联分析（TWAS）和共定位分析、精细映射以及对AD GWAS变异的额外注释，以在已知和提示的AD风险位点上识别出123个候选基因。与人类阿尔茨海默病大脑转录组数据进行比较确认了许多这些候选基因在人类AD中失调，并且与神经病理学相关。然后我们在两个已经建立的良好果蝇AD模型中测试了所有可用的同源物，这两个模型分别表达野生型tau蛋白或分泌β-淀粉样蛋白（β42）。实验扰动60个可用候选者中的任何一个，在一个或两个果蝇模型中发现了46个影响神经元功能的基因。这些基因中有18种的效果与TWAS预测一致，即在人类中错误表达的方向增加AD风险会加剧行为障碍。逆转其中11个基因（MTCH2、ELL、TAP2、HDC、DMWD、MYCL、SLC4A9、ABCA7、CSTF1、PTK2B和CD2AP）的异常下调或上调在体内表现出神经保护作用。我们进一步研究了MTCH2并发现它调节果蝇大脑中tau蛋白稳态，并减少人类神经前体细胞中的tau积累。这种系统性、整合的方法有效地优先选择GWAS位点上的基因，揭示出有前景的AD相关候选者作为风险因素或治疗干预目标进行进一步调查。

    关键词：阿尔茨海默病；MTCH2；SPI1；TWAS；行为筛查；纵向转录组学；神经保护作用。

    关键词：计算优先级; 阿尔茨海默病; tau蛋白

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    期刊名：American journal of human genetics

    缩写：AM J HUM GENET

    ISSN：0002-9297

    e-ISSN：1537-6605

    IF/分区：8.1/Q1

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    Computational and functional prioritization identifies genes that rescue behavior and reduce tau protein in fly and human cell models of Alzheimer disease