Abstract
BACKGROUND: Shorter stature has been phenotypically linked to increased prevalence of schizophrenia (SCZ), but the nature of this association is unknown.
METHODS: Using genome-wide genetic data from 513,398 participants, we studied the SCZ-height relationship on a genetic level. Applying novel genetic methods and tools, we analyzed gene sets, tissue types, cell types, local genetic correlation, conditional genetic analyses, and fine-mapping of effector genes to scrutinize the SCZ-height relationship.
RESULTS: We identified 142 genes statistically associated with both SCZ and height and found enrichment in 3 functional gene sets. Genetic annotations implicated the pituitary and specifically mesenchymal stem cells for height and thyrotropic cells for SCZ. While the global SCZ-height genetic correlation was nonsignificant, 9 genomic regions showed robust local genetic correlations (7 negative, 6 in the major histocompatibility complex [MHC] region). The shared genetic signal for SCZ and height within the 6 MHC regions was partially explained by mutual genetic overlap with white blood cell count, particularly lymphocytes. Fine-mapping prioritized 3 shared effector genes (GIGYF2, HLA-C, and LIN28B) involved in immune response sensitivity and the development of immune and pituitary cell types.
CONCLUSIONS: Overall, our findings suggest an involvement during height development of thyrotropic cells and immune response sensitivity that contribute toward the risk of SCZ.