New aQTL SNPs for the CYP2D6 identified by a novel mediation analysis of genome-wide SNP arrays, gene expression arrays, and CYP2D6 activity

Abstract

Background: The genome-wide association studies (GWAS) have been successful during the last few years. A key challenge is that the interpretation of the results is not straightforward, especially for transacting SNPs. Integration of transcriptome data into GWAS may provide clues elucidating the mechanisms by which a genetic variant leads to a disease.

Methods: Here, we developed a novel mediation analysis approach to identify new expression quantitative trait loci (eQTL) driving CYP2D6 activity by combining genotype, gene expression, and enzyme activity data.

Results: 389,573 and 1,214,416 SNP-transcript-CYP2D6 activity trios are found strongly associated (P < 10⁻⁵, FDR = 16.6% and 11.7%) for two different genotype platforms, namely, Affymetrix and Illumina, respectively. The majority of eQTLs are trans-SNPs. A single polymorphism leads to widespread downstream changes in the expression of distant genes by affecting major regulators or transcription factors (TFs), which would be visible as an eQTL hotspot and can lead to large and consistent biological effects. Overlapped eQTL hotspots with the mediators lead to the discovery of 64 TFs.

Conclusions: Our mediation analysis is a powerful approach in identifying the trans-QTL-phenotype associations. It improves our understanding of the functional genetic variations for the liver metabolism mechanisms.

Figure 1

Mediation test.

Figure 2

eQTL visualization. The main plot at the bottom is the scatter plot of the eQTL-transcript association. Each dot denotes a significant association between a SNP and a transcript (P value <10⁻⁵). Gray color shows the level of significance where dark means more significant association. SNPs are arranged according to their chromosomal loci along the X-axis from chromosome 1 to 22, and genes are arranged along Y-axis in the same way. The dots along diagonal line indicate cis-eQTLs, otherwise, trans-eQTLs. The counts plot in the middle gives the number of genes that a SNP correlated with significantly (P value <10⁻⁵). Large size means more genes associated with that SNP. The −log₁₀ (FDR) plot at the top presents the enrichment score of a SNP associated with multiple transcripts comparing with that by chance. SNP has a large circle in counts plot and a high enrichment score in −log₁₀ (FDR) plot which indicates eQTL hotspots.