Investigating the shared genetic architecture between schizophrenia and sex hormone traits

Abstract

Sex hormones are involved in schizophrenia pathogenesis; however, their direction and genetic overlap remain unknown. By leveraging summary statistics from large-scale genome-wide association studies, we quantified the shared genetic architecture between schizophrenia and four sex hormone traits. Linkage disequilibrium score regression and bivariate causal mixture modeling strategies showed significant positive correlations between sex hormone-binding globulin (SHBG), total testosterone, and schizophrenia, while bioavailable testosterone and schizophrenia were negatively correlated. Estradiol showed a weak positive correlation with schizophrenia, with little polygenic overlap. The conjunctional false discovery rate method identified 303 lead single-nucleotide polymorphisms (SNPs) in jointly shared genomic loci between schizophrenia and SHBG, with 130, 52, and 9 SNPs shared between schizophrenia and total testosterone, bioavailable testosterone, and estradiol, respectively. Functional annotation suggests that mitotic sister chromatid segregation and N-glycan biosynthesis may be involved in common mechanisms underlying sex hormone regulation and schizophrenia onset. In conclusion, this study clarified the inherent relationships between schizophrenia and sex hormone traits, highlighted the roles of mitotic sister chromatid segregation and N-glycan biosynthesis in the pathogenesis of schizophrenia, and delivered potential targets for further validation.

Fig. 1. Polygenic overlap between schizophrenia (SCZ) and sex hormone (SH) traits.

Venn diagrams depicting the unique and shared variants associated with SCZ and SH traits. The value and circle size reflect the extent of polygenicity for each trait. Conditional Q‑Q plots of nominal versus empirical -log10 transformed P values in the primary phenotype as a function of significance of SNP associations with the secondary phenotype at the level of P < 1.00, P < 0.1, P < 0.01, and P < 0.001. The dashed line is the expected Q‑Q plot under the null hypothesis. SHBG sex hormone-binding globulin. Total T total testosterone. Bioavailable T bioavailable testosterone. * The results are only for males as data for females is not available.

Fig. 2. Circular Manhattan plot showing common genetic variants jointly associated with schizophrenia and sex hormone traits.

Circular Manhattan plot depicting the -log10 conjFDR values for SNPs jointly associated with schizophrenia and sex hormone traits. The red dashed line represents the threshold for significant association set at conjFDR < 0.05. The circles from the outside to the inside successively are SHBG, total testosterone, bioavailable testosterone, and estradiol. * The results are only for males as data for females is not available.

Fig. 3. MAGMA gene-set analysis for genes jointly associated with schizophrenia and sex hormone traits.

Bar diagrams showing the enriched gene sets between schizophrenia and (A) SHBG, and (B) Testosterone on three important databases, specifically, the Gene Ontology-Biological Process (GO BP), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and the Reactome Pathway Database (REACTOME). No significant gene sets are enriched on the three databases for shared genes of schizophrenia with bioavailable testosterone and estradiol.