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

Guanglong Jiang, Arindom Chakraborty, Zhiping Wang, Malaz Boustani, Yunlong Liu, Todd Skaar, Lang Li

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Article number493019
JournalBioMed Research International
Volume2013
DOIs
StatePublished - 2013

Fingerprint

Cytochrome P-450 CYP2D6
Quantitative Trait Loci
Gene expression
Single Nucleotide Polymorphism
Genes
Genome-Wide Association Study
Genome
Gene Expression
Transcription Factors
Genotype
Enzyme activity
Polymorphism
Transcriptome
Metabolism
Liver
Phenotype
Enzymes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

New aQTL SNPs for the CYP2D6 identified by a novel mediation analysis of genome-wide SNP arrays, gene expression arrays, and CYP2D6 activity. / Jiang, Guanglong; Chakraborty, Arindom; Wang, Zhiping; Boustani, Malaz; Liu, Yunlong; Skaar, Todd; Li, Lang.

In: BioMed Research International, Vol. 2013, 493019, 2013.

Research output: Contribution to journalArticle

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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.",
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AU - Jiang, Guanglong

AU - Chakraborty, Arindom

AU - Wang, Zhiping

AU - Boustani, Malaz

AU - Liu, Yunlong

AU - Skaar, Todd

AU - Li, Lang

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