Background.The genome-wide association studies (GWAS) have been successful during the last few years. A key challenge is that\r\nthe interpretation of the results is not straightforward, especially for transacting SNPs. Integration of transcriptome data intoGWAS\r\nmay provide clues elucidating the mechanisms by which a genetic variant leads to a disease. Methods. Here, we developed a novel\r\nmediation analysis approach to identify new expression quantitative trait loci (eQTL) driving CYP2D6 activity by combining\r\ngenotype, gene expression, and enzyme activity data. Results. 389,573 and 1,214,416 SNP-transcript-CYP2D6 activity trios are\r\nfound strongly associated (?? < 10-5, FDR = 16.6% and 11.7%) for two different genotype platforms, namely, Affymetrix and\r\nIllumina, respectively. The majority of eQTLs are trans-SNPs. A single polymorphism leads to widespread downstream changes\r\nin the expression of distant genes by affecting major regulators or transcription factors (TFs), which would be visible as an eQTL\r\nhotspot and can lead to large and consistent biological effects. Overlapped eQTL hotspots with the mediators lead to the discovery\r\nof 64 TFs. Conclusions. Our mediation analysis is a powerful approach in identifying the trans-QTL-phenotype associations. It\r\nimproves our understanding of the functional genetic variations for the liver metabolism mechanisms.
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