Professor University of Minnesota Minneapolis, Minnesota
Sex differences have been widely observed in human health. However, little is known about the underlying mechanism behind these observed sex differences. We hypothesized that sex-differentiated genetic effects are contributors of these phenotypic differences. Focusing on a collection of drug metabolism enzymes and transporters (DMET) genes, we discovered sex differentiated genetic regulatory mechanisms between these genes and human complex traits. Here, we showed 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 were reflected in the levels of gene expression and endogenous serum biomarkers. Through Mendelian Randomization analysis, we identified putative sex-differentiated causal effects in each sex separately. Furthermore, we identified and validated sex differential gene expression of a subset of DMET genes in human liver samples. We observed higher protein abundance and enzyme activity of CYP1A2 in male-derived liver microsomes, which led 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.
Learning Objectives:
Learn that sex differences in genetic effects on human complex traits exist at both genome-wide and regional level.
Identify various sex differential genetic regulatory mechanisms associated with DMET genes.
Learn how sex-specific DMET genetic regulation may lead to sex differences in drug side effects.