Immune-developmental processes contribute to schizophrenia risk: insights from a genetic overlap study with height.

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, 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 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 development of immune and pituitary cell-types.

Conclusions: Overall, our findings suggest an involvement during height-development of thyrotropic cells and immune response sensitivity contributing towards risk of SCZ.