Yang Hsin-Chou, Lin Chien-Wei, Chen Chia-Wei, Chen James J
Institute of Statistical Science, Academia Sinica, No 128, Academia Road, Section 2, Nankang, Taipei, Taiwan.
BMC Genomics. 2014 Apr 29;15:319. doi: 10.1186/1471-2164-15-319.
Gene-based analysis has become popular in genomic research because of its appealing biological and statistical properties compared with those of a single-locus analysis. However, only a few, if any, studies have discussed a mapping of expression quantitative trait loci (eQTL) in a gene-based framework. Neither study has discussed ancestry-informative eQTL nor investigated their roles in pharmacogenetics by integrating single nucleotide polymorphism (SNP)-based eQTL (s-eQTL) and gene-based eQTL (g-eQTL).
In this g-eQTL mapping study, the transcript expression levels of genes (transcript-level genes; T-genes) were correlated with the SNPs of genes (sequence-level genes; S-genes) by using a method of gene-based partial least squares (PLS). Ancestry-informative transcripts were identified using a rank-score-based multivariate association test, and ancestry-informative eQTL were identified using Fisher's exact test. Furthermore, key ancestry-predictive eQTL were selected in a flexible discriminant analysis. We analyzed SNPs and gene expression of 210 independent people of African-, Asian- and European-descent. We identified numerous cis- and trans-acting g-eQTL and s-eQTL for each population by using PLS. We observed ancestry information enriched in eQTL. Furthermore, we identified 2 ancestry-informative eQTL associated with adverse drug reactions and/or drug response. Rs1045642, located on MDR1, is an ancestry-informative eQTL (P = 2.13E-13, using Fisher's exact test) associated with adverse drug reactions to amitriptyline and nortriptyline and drug responses to morphine. Rs20455, located in KIF6, is an ancestry-informative eQTL (P = 2.76E-23, using Fisher's exact test) associated with the response to statin drugs (e.g., pravastatin and atorvastatin). The ancestry-informative eQTL of drug biotransformation genes were also observed; cross-population cis-acting expression regulators included SPG7, TAP2, SLC7A7, and CYP4F2. Finally, we also identified key ancestry-predictive eQTL and established classification models with promising training and testing accuracies in separating samples from close populations.
In summary, we developed a gene-based PLS procedure and a SAS macro for identifying g-eQTL and s-eQTL. We established data archives of eQTL for global populations. The program and data archives are accessible at http://www.stat.sinica.edu.tw/hsinchou/genetics/eQTL/HapMapII.htm. Finally, the results from our investigations regarding the interrelationship between eQTL, ancestry information, and pharmacodynamics provide rich resources for future eQTL studies and practical applications in population genetics and medical genetics.
基于基因的分析在基因组研究中已变得流行，因为与单基因座分析相比，它具有吸引人的生物学和统计学特性。然而，即便有研究讨论了在基于基因的框架下表达定量性状基因座（eQTL）的定位，数量也很少。尚无研究讨论祖先信息丰富的eQTL，也未通过整合基于单核苷酸多态性（SNP）的eQTL（s-eQTL）和基于基因的eQTL（g-eQTL）来研究它们在药物遗传学中的作用。
在这项g-eQTL定位研究中，通过使用基于基因的偏最小二乘法（PLS），将基因的转录本表达水平（转录本水平基因；T-基因）与基因的SNP（序列水平基因；S-基因）相关联。使用基于秩得分的多变量关联检验识别祖先信息丰富的转录本，并使用Fisher精确检验识别祖先信息丰富的eQTL。此外，在灵活判别分析中选择关键的祖先预测性eQTL。我们分析了210名非洲、亚洲和欧洲血统的独立个体的SNP和基因表达。通过使用PLS，我们为每个群体鉴定了大量顺式和反式作用的g-eQTL和s-eQTL。我们观察到eQTL中富集了祖先信息。此外，我们鉴定了2个与药物不良反应和/或药物反应相关的祖先信息丰富的eQTL。位于MDR1上的Rs1045642是一个祖先信息丰富的eQTL（使用Fisher精确检验，P = 2.13E-13），与对阿米替林和去甲替林的药物不良反应以及对吗啡的药物反应相关。位于KIF6中的Rs20455是一个祖先信息丰富的eQTL（使用Fisher精确检验，P = 2.76E-23），与对他汀类药物（如普伐他汀和阿托伐他汀）的反应相关。还观察到了药物生物转化基因的祖先信息丰富的eQTL；跨群体顺式作用表达调节因子包括SPG7、TAP2、SLC7A7和CYP4F2。最后，我们还鉴定了关键的祖先预测性eQTL，并建立了在区分来自相近群体的样本方面具有良好训练和测试准确性的分类模型。
总之，我们开发了一种基于基因的PLS程序和一个SAS宏来识别g-eQTL和s-eQTL。我们建立了全球人群的eQTL数据档案。该程序和数据档案可在http://www.stat.sinica.edu.tw/hsinchou/genetics/eQTL/HapMapII.htm获取。最后，我们关于eQTL、祖先信息和药效学之间相互关系的研究结果为未来的eQTL研究以及群体遗传学和医学遗传学的实际应用提供了丰富资源。
