Entschlüsselung der spender- und zelltypspezifischen Interaktionen mit Schizophrenie-Risikovarianten
Molekulare Biologie und Physiologie von Nerven- und Gliazellen
Zusammenfassung der Projektergebnisse
Schizophrenia (SZ) is a common (1%), highly heritable (80%) polygenic disorder that imposes an immense burden on patients and society. A substantial proportion of risk arises through interactions between over 145 SZ common risk loci of small effect in several distinct brain cell types. The extent to which the additive impact of each additional common risk variant is dependent upon the risk factors already present in an individual is unknown. Here, we explore how the functional impact of one common variant, FURIN rs4702, varies between donors and neural cell types. We applied CRISPR-editing to engineer the risk variant, rs4702, in human pluripotent stem cells (hiPSCs), to study the effect in isogenic neural cell types implicated in SZ during development, specifically astrocytes, glutamatergic neurons and GABAergic neurons. To test the impact of donor background and risk synergy, rs4702 was introduced into high and low SZ polygenic risk score (PRS) donor lines. To test the functional effect of allelic conversion at rs4702 in combination with PRS, altered FURIN expression, neurite length, synaptic punctae and weighted mean firing rate were assessed. Our data suggests that the impact of rs4702 is dependent on the genetic background, which influences the amplitude of the FURIN eQTL. However, in our preliminary analysis, we could not find a strong correlation between eQTL penetrance and SZ PRS in the genomic background. Our long-term objective is to uncover the celltype-specific convergence and synergy between the many risk variants linked to SZ and identify other factors, that might impact eQTL penetrance.
