Impact of rare and common genetic risk variants for schizophrenia on microglia activation

A. Vernon^1,. ¹Institute of Psychiatry- King’s College London, Basic and Clinical Neuroscience, London, United Kingdom.

Genes involves in neuro-immune and inflammatory signalling pathways are observed to be upregulated in post-mortem brain tissue in schizophrenia (SZ), autism spectrum condition (ASC) and Alzheimer’s disease (AD). Yet, cell-specific enrichment of these upregulated neuro-immune genes is only found for AD, consistent with the localization of genome-wide association signals for AD within microglia. This suggests a hypothesis that neural-immune dysregulation in SZ and ASC may be compensatory and not a primary pathological mechanism. Human induced pluripotent stem cell (hiPSC)-derived microglia provide a relevant model to test this hypothesis. We took advantage of this to compare transcriptional and functional differences in hiPSC-derived microglia from individuals with 22q11.2 deletion syndrome (ds), a rare copy number variant (CNV) associated with significantly increased risk for SZ and ASC (N=3 donors) relative to healthy, neurotypical controls (N=5 donors), matched for chromosomal sex (XX vs. XY). In this talk I will present our findings from these comparisons at the transcriptional, secretory, functional (phagocytosis) and metabolic level. Our data using stem cell derived models provide the first evidence that 22q11.2ds impacts on human microglia form and function in vitro. Although further studies are required, these data suggest that microglial activation could represent a primary, rather than secondary pathology and may influence neuropsychiatric disease manifestation in the context of 22q11.2ds