TY - JOUR
T1 - Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes
AU - Huang, Yingbo
AU - Shan, Yuting
AU - Zhang, Weijie
AU - Lee, Adam M.
AU - Li, Feng
AU - Stranger, Barbara E.
AU - Huang, R. Stephanie
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-023-35808-6
DO - 10.1038/s41467-023-35808-6
M3 - Article
C2 - 36635277
AN - SCOPUS:85146195230
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 175
ER -