LA-GEM: imputation of gene expression with incorporation of Local Ancestry
LA-GEM: imputation of gene expression with incorporation of Local Ancestry
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LA-GEM：结合当地祖先的基因表达估算
DOI：
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发表时间：
2023
影响因子：
--
通讯作者：
M. Perera
中科院分区：
文献类型：
--
作者：
Mrinal Mishra;Layan Nahlawi;Yizhen Zhong;T. De;Guang Yang;Cristina Alarcon;M. Perera
基因植入和TWAS已成为基因组学医学发现领域的主要内容；帮助鉴定其调控作用可能有助于疾病易感性的基因。然而，建立这些方法的人群绝大多数是欧洲血统。这意味着存在于非欧洲人群，特别是非洲血统人群中的独特调控变异可能不包括在当前的模型中。此外，非裔美国人是一个混血儿，在他们的基因组中混合了欧洲和非洲的片段。目前还没有将本地祖先对基因表达植入的影响纳入基因植入模型。因此，我们创建了LA-GEM，在60个非裔美国人肝细胞原代培养的队列中进行了培训和测试。独特的是，LA-GEM在预测基因表达时包含了本地祖先推断。我们比较了LA-GEM和PrediXcan训练相同数据集（不包括本地祖先）的性能，我们能够可靠地预测2559个基因的表达（LA-GEM中的1326个，PrediXcan中的1236个）。其中，546个基因是LA-GEM独有的，包括对药物代谢至关重要的CYP3A5基因。我们对两个具有药物基因组学表型信息的非裔美国人临床队列进行了TWAS分析，以确定新的基因关联。在我们的IWPC华法林队列中，我们确定了17个转录组范围内的显著命中。在氯吡格雷队列中没有达到预先指定的显著水平的基因。我们确实看到了RAS3A与P2RY12反应单位（PRU）的相关性，PRU是抗血小板治疗反应的临床指标。该方法证明了将LA纳入混合种群研究的必要性。
Gene imputation and TWAS have become a staple in the genomics medicine discovery space; helping to identify genes whose regulation effects may contribute to disease susceptibility. However, the cohorts on which these methods are built are overwhelmingly of European Ancestry. This means that the unique regulatory variation that exist in non-European populations, specifically African Ancestry populations, may not be included in the current models. Moreover, African Americans are an admixed population, with a mix of European and African segments within their genome. No gene imputation model thus far has incorporated the effect of local ancestry (LA) on gene expression imputation. As such, we created LA-GEM which was trained and tested on a cohort of 60 African American hepatocyte primary cultures. Uniquely, LA-GEM include local ancestry inference in its prediction of gene expression. We compared the performance of LA-GEM to PrediXcan trained the same dataset (with no inclusion of local ancestry) We were able to reliably predict the expression of 2559 genes (1326 in LA-GEM and 1236 in PrediXcan). Of these, 546 genes were unique to LA-GEM, including the CYP3A5 gene which is critical to drug metabolism. We conducted TWAS analysis on two African American clinical cohorts with pharmacogenomics phenotypic information to identity novel gene associations. In our IWPC warfarin cohort, we identified 17 transcriptome-wide significant hits. No gene reached are prespecified significance level in the clopidogrel cohort. We did see suggestive association with RAS3A to P2RY12 Reactivity Units (PRU), a clinical measure of response to anti-platelet therapy. This method demonstrated the need for the incorporation of LA into study in admixed populations.
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影响因子：
9.8
作者：
Mancuso, Nicholas;Shi, Huwenbo;Pasaniuc, Bogdan
通讯作者：
Pasaniuc, Bogdan
DOI：
10.1038/nrc2960
发表时间：
2010-12
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.6
作者：
Zhang Y;Parmigiani G;Johnson WE
通讯作者：
Johnson WE
影响因子：
15.9
作者：
Stefanini, Lucia;Paul, David S.;Bergmeier, Wolfgang
通讯作者：
Bergmeier, Wolfgang
影响因子：
9.8
作者：
Maples, Brian K.;Gravel, Simon;Bustamante, Carlos D.
通讯作者：
Bustamante, Carlos D.