Applying genome-wide gene-based expression quantitative trait locus mapping to study population ancestry and pharmacogenetics.

BACKGROUND

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).

RESULTS

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.

CONCLUSIONS

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.