Copy number variation profiling in pharmacogenes using panel-based exome resequencing and correlation to human liver expression

  • Roman TremmelEmail author
  • Kathrin Klein
  • Florian Battke
  • Sarah Fehr
  • Stefan Winter
  • Tim Scheurenbrand
  • Elke Schaeffeler
  • Saskia Biskup
  • Matthias Schwab
  • Ulrich M. Zanger
Original Investigation


Structural variants including copy number variations (CNV) have gained widespread attention, especially in pharmacogenomics but for several genes functional relevance and clinical evidence are still lacking. Detection of CNVs in next-generation sequencing data is challenging but offers widespread applications. We developed a cohort-based CNV detection workflow to extract CNVs from read counts of targeted NGS of 340 genes involved in absorption, distribution, metabolism and excretion (ADME) of drugs. We applied our method to 150 human liver tissue samples and correlated identified CNVs to mRNA expression levels. In total, we identified 445 deletions (73%) and 167 duplications (27%) in 36 pharmacogenes including all well-known CNVs of CYPs, GSTs, SULTs, UGTs, numerous described rare CNVs of CYP2E1, SLC16A3 or UGT2B15 as well as novel observations, e.g., for SLC22A12, SLC22A17 and GPS2 (G Protein Pathway Suppressor 2). We were able to fine-map complex CNVs of CYP2A6 and CYP2D6 with exon resolution. Correlation analysis confirmed known expression patterns for common CNVs and suggested an influence on expression variability for some rare CNVs. Our straightforward CNV detection workflow can be easily applied to any NGS coverage data and helped to analyze CNVs in an ADME-NGS panel of 340 pharmacogenes to improve genotype–phenotype correlations.



We thank Dr. Florian Büttner for statistical expertise and discussions. The excellent technical assistance of Igor Liebermann is gratefully acknowledged. This study was supported by the Robert Bosch Foundation, Stuttgart, Germany and the European Commission Horizon 2020-PHC-2015 Grant U-PGx 668353.

Compliance with ethical standards

Conflict of interest

SF, FB, TS, and SB were employed by CeGaT GmbH, Tübingen. The remaining authors declare that they have no competing interests.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Roman Tremmel
    • 1
    • 2
    Email author
  • Kathrin Klein
    • 1
    • 2
  • Florian Battke
    • 3
    • 4
  • Sarah Fehr
    • 3
    • 4
  • Stefan Winter
    • 1
    • 2
  • Tim Scheurenbrand
    • 3
    • 4
  • Elke Schaeffeler
    • 1
    • 2
    • 5
  • Saskia Biskup
    • 3
    • 4
  • Matthias Schwab
    • 1
    • 5
    • 6
  • Ulrich M. Zanger
    • 1
    • 2
  1. 1.Dr. Margarete Fischer-Bosch-Institute of Clinical PharmacologyStuttgartGermany
  2. 2.University of TübingenTübingenGermany
  3. 3.CeGaT GmbHTübingenGermany
  4. 4.Praxis für Humangenetik TübingenTübingenGermany
  5. 5.iFIT Cluster of Excellence, University of TübingenTübingenGermany
  6. 6.Departments of Clinical Pharmacology, Pharmacy and BiochemistryUniversity of TübingenTübingenGermany

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