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Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes

Author

Listed:
  • Yingbo Huang

    (University of Minnesota)

  • Yuting Shan

    (University of Minnesota)

  • Weijie Zhang

    (University of Minnesota)

  • Adam M. Lee

    (University of Minnesota)

  • Feng Li

    (University of Minnesota
    eGenesis, Inc)

  • Barbara E. Stranger

    (Northwestern University Feinberg School of Medicine)

  • R. Stephanie Huang

    (University of Minnesota)

Abstract

Sex differences have been widely observed in human health. However, little is known about the underlying mechanism behind these observed sex differences. We hypothesize that sex-differentiated genetic effects are contributors of these phenotypic differences. Focusing on a collection of drug metabolism enzymes and transporters (DMET) genes, we discover sex-differentiated genetic regulatory mechanisms between these genes and human complex traits. Here, we show that sex-differentiated genetic effects were present at genome-level and at DMET gene regions for many human complex traits. These sex-differentiated regulatory mechanisms are reflected in the levels of gene expression and endogenous serum biomarkers. Through Mendelian Randomization analysis, we identify putative sex-differentiated causal effects in each sex separately. Furthermore, we identify and validate sex differential gene expression of a subset of DMET genes in human liver samples. We observe higher protein abundance and enzyme activity of CYP1A2 in male-derived liver microsomes, which leads to higher level of an active metabolite formation of clozapine, a commonly prescribed antipsychotic drug. Taken together, our results demonstrate the presence of sex-differentiated genetic effects on DMET gene regulation, which manifest in various phenotypic traits including disease risks and drug responses.

Suggested Citation

  • Yingbo Huang & Yuting Shan & Weijie Zhang & Adam M. Lee & Feng Li & Barbara E. Stranger & R. Stephanie Huang, 2023. "Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35808-6
    DOI: 10.1038/s41467-023-35808-6
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    2. Chris Wallace, 2021. "A more accurate method for colocalisation analysis allowing for multiple causal variants," PLOS Genetics, Public Library of Science, vol. 17(9), pages 1-11, September.
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