Schizotypy, Psychosis Proneness, and the Polygenic Risk for Schizophrenia and Resilience.

BACKGROUND AND HYPOTHESIS: Schizotypy is a well-established phenotype for psychosis proneness and risk. Yet, its genetic underpinnings and relations to genetic bases of the schizophrenia spectrum are not well understood owing to conflicting findings. In a deep phenotyping approach, we hypothesized that genetic markers of risk for and to schizophrenia are differentially associated with (trait-level) dimensions of schizotypy and (state-level) prodromal symptoms.

STUDY DESIGN: In 367 (130 male, 237 female) psychiatrically healthy young adults, we assessed multiple schizotypy instruments (OLIFE, SPQ-B, Multidimensional Schizotypy Scales), aggregated into composite scores, and a measure of prodromal symptoms (PQ-16). Those were tested for direct and interactive associations with the polygenic risk score (PRS) for schizophrenia and a novel PRS for resilience to schizophrenia.

STUDY RESULTS: Both prodromal symptom number (rho = 0.16, pcorr = .018) and distress (rho = 0.14, pcorr = .027) were positively related to the schizophrenia PRS. Positive schizotypy showed a similar association but did not remain significant after correction (rho = 0.11, pcorr = .082). Schizophrenia PRS and disorganized schizotypy had a negative interactive effect on prodromal symptom distress (b = -0.10, pcorr = .048). The resilience score did not show any significant associations with any of the measures.

CONCLUSIONS: These results further support the idea of a (partially) shared genetic basis of schizophrenia and nonclinical, predominantly positive expressions of the psychosis spectrum but also indicate relevant distinctions between the 2, possibly related to other modulating factors or general (transdiagnostic) psychopathological risk. In line with previous findings, effects seem to be more robust for state- than trait-level markers, but these may also be influencing each other.

© The Author(s) 2025. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

PMID: 40037822