Integrative Network-Based Analysis Reveals Gene Networks and Novel Drug Repositioning Candidates for Alzheimer Disease.
Integrative Network-Based Analysis Reveals Gene Networks and Novel Drug Repositioning Candidates for Alzheimer Disease.
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DOI：
10.1212/nxg.0000000000000622
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Derks EM
中科院分区：
文献类型：
--
作者：
Gerring ZF;Gamazon ER;White A;Derks EM
整合全基因组关联研究数据与组织特异性基因表达信息，以确定阿尔茨海默病的共表达网络，生物学途径和药物重新定位候选人。在基因型-组织表达研究中，我们将阿尔茨海默病的全基因组关联汇总统计与脑组织样本的组织特异性基因共表达网络相结合。我们鉴定了富含阿尔茨海默病遗传信号的基因共表达网络，并使用生物途径分析表征了相关网络。随后将疾病相关模块用作计算药物重新定位分析的分子底物，其中我们（1）在阿尔茨海默病相关模块内估算遗传调节基因表达;（2）将估算的基因表达水平与来自连接图的药物基因签名整合，以鉴定使阿尔茨海默病相关的失调基因表达正常化的化合物;以及（3）基于药物化合物和作用机制使失调的表达标记正常化的程度，对药物化合物和作用机制进行优先排序。阿尔茨海默病的遗传因素在参与免疫反应的脑基因共表达网络中富集。计算药物重新定位分析疾病相关网络内的表达变化，检索已知的阿尔茨海默病药物（例如，美金刚）以及生物学上有意义的药物类别（例如，谷氨酸受体拮抗剂）。我们的研究结果改善了阿尔茨海默病遗传数据的生物学解释，并提供了一个潜在的抗痴呆药物重新定位候选人的列表，其疗效应在功能验证研究中进行调查。
To integrate genome-wide association study data with tissue-specific gene expression information to identify coexpression networks, biological pathways, and drug repositioning candidates for Alzheimer disease. We integrated genome-wide association summary statistics for Alzheimer disease with tissue-specific gene coexpression networks from brain tissue samples in the Genotype-Tissue Expression study. We identified gene coexpression networks enriched with genetic signals for Alzheimer disease and characterized the associated networks using biological pathway analysis. The disease-implicated modules were subsequently used as a molecular substrate for a computational drug repositioning analysis, in which we (1) imputed genetically regulated gene expression within Alzheimer disease implicated modules; (2) integrated the imputed gene expression levels with drug-gene signatures from the connectivity map to identify compounds that normalize dysregulated gene expression underlying Alzheimer disease; and (3) prioritized drug compounds and mechanisms of action based on the extent to which they normalize dysregulated expression signatures. Genetic factors for Alzheimer disease are enriched in brain gene coexpression networks involved in the immune response. Computational drug repositioning analyses of expression changes within the disease-associated networks retrieved known Alzheimer disease drugs (e.g., memantine) as well as biologically meaningful drug categories (e.g., glutamate receptor antagonists). Our results improve the biological interpretation of genetic data for Alzheimer disease and provide a list of potential antidementia drug repositioning candidates for which the efficacy should be investigated in functional validation studies.
DOI：
10.1007/s10495-017-1405-z
发表时间：
2017-10
期刊：
Apoptosis : an international journal on programmed cell death
影响因子：
--
作者：
García-Laínez G;Sancho M;García-Bayarri V;Orzáez M
通讯作者：
Orzáez M