Unveiling molecular underlying causes of observed sex differences in human complex traits and cancer.

Abstract

Sex differences have been observed in human health, particularly in disease diagnosis and therapeutic response. Research has shown sex to be a modifier of human genetics—for instance, sex chromosomes play roles in regulating health. However, the underlying molecular mechanisms behind many observed sex differences in complex human traits remain largely unexplored.In this thesis, I present my work into two focuses: 1) Exploring sex differences in the genetic effects of drug metabolism enzymes and transporters (DMET) genes on human complex traits; and 2) Investigating the sex differences in molecular mechanisms in cancers. In the first area, we demonstrate that sex-differentiated genetic effects exist at the genome level and within DMET gene regions across many human complex traits. These mechanisms are evident in gene expression levels and serum biomarker concentrations. Through Mendelian Randomization analysis, we identify potential sex-specific causal effects. Additionally, we confirm sex-differential gene expression for a subset of DMET genes in human liver samples, noting a higher protein abundance and enzyme activity of CYP1A2 in liver microsomes from males, which results in increased formation of an active metabolite of clozapine, a widely used antipsychotic drug. Our findings reveal the existence of sex-differentiated genetic effects on DMET gene regulation, impacting various phenotypic traits, including disease risks and drug responses. For the second focus, we compile a review summarizing current knowledge on sex differences in therapeutic responses to Non-Small Cell Lung Cancer (NSCLC). We find that women generally have better progression-free survival from first-generation anti-epidermal growth factor receptor (EGFR) treatments than men. However, the discussion on sex differences in response to immunotherapy remains ongoing, with outcomes appearing to depend on treatment settings, patient characteristics, and molecular features. Notably, considering sex as a biological factor in biomarker discovery offers new insights into immunotherapy responses. Furthermore, we investigate sex differences in adult diffuse glioma (ADG), where clinical settings have well-established differences. By systematically analyzing the transcriptome of ADG, we find that mutations in isocitrate dehydrogenase (IDH) genes and the tumor microenvironment significantly influence sex-differential molecular profiles. Distinct molecular features between male and female tumors, particularly in IDH mutant and wild-type cohorts, suggest that these differences may be due to varied cellular compositions between sexes. Single-cell RNA sequencing data reveal distinct patterns of sex differences in cell states, compositions, and interactions within IDH mutant and wild-type tumors. Additionally, a comparison of molecular changes in primary and recurrent ADG samples highlights sex-specific differences in molecular characteristics and cellular compositions of recurrent tumors, providing a comprehensive characterization of sex differences in ADG and novel insights into glioma disease progression by sex. This work provides both evidence and frameworks for investigating sex differences in human complex traits and cancers.