Immune-Developmental Processes Contribute to Schizophrenia Risk: Insights From a Genetic Overlap Study With Height

Shorter stature has been phenotypically linked to increased prevalence of schizophrenia (SCZ), but the nature of this association is unknown.

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.

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.

Overall, our findings suggest an involvement during height development of thyrotropic cells and immune response sensitivity that contribute toward the risk of SCZ.