RNA-sequencing of peripheral whole blood of individuals at ultra-high-risk for psychosis – A longitudinal perspective

Background: The peripheral blood is an attractive source of prognostic biomarkers for psychosis conversion. There is limited research on the transcriptomic changes associated with psychosis conversion in the peripheral whole blood. Study Design: We performed RNA-sequencing of peripheral whole blood from 65 ultra-high-risk (UHR) participants and 70 healthy control participants recruited in the Longitudinal Youth-at-Risk Study (LYRIKS) cohort. 13 UHR participants converted in the study duration. Samples were collected at 3 timepoints, at 12-months interval across a 2-year period. We examined whether the genes differential with psychosis conversion contain schizophrenia risk loci. We then examined the functional ontologies and GWAS associations of the differential genes. We also identified the overlap between differentially expressed genes across different comparisons. Study results: Genes containing schizophrenia risk loci were not differentially expressed in the peripheral whole blood in psychosis conversion. The differentially expressed genes in psychosis conversion are enriched for ontologies associated with cellular replication. The differentially expressed genes in psychosis conversion are associated with non-neurological GWAS phenotypes reported to be perturbed in schizophrenia and psychosis but not schizophrenia and psychosis phenotypes themselves. We found minimal overlap between the genes differential with psychosis conversion and the genes that are differential between pre-conversion and non-conversion samples. Conclusion: The associations between psychosis conversion and peripheral blood-based biomarkers are likely to be indirect. Further studies to elucidate the mechanism behind potential indirect associations are needed.