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Differential Association of Schizotypy Dimensions With Brain Structural Connectivity and Moderation by Schizophrenia Polygenic Risk.

Schizophrenia bulletin

Authors: Jonas Hoffmann, Tina Meller, Carlo Maj, Per Hoffmann, Andreas J Forstner, Markus M Nöthen, Igor Nenadić

OBJECTIVE: Schizotypy as a psychosis proneness marker has facilitated the study of schizophrenia spectrum models, linking phenotypic psychosis risk to brain structural and functional variation. However, association studies to structural connectome markers are limited and often do not consider relations to genetic risk. We tested the hypothesis that dimensions of schizotypy (rather than overall phenotype risk burden) are related to fiber tract integrity and that this is moderated by polygenic schizophrenia risk (or resilience).

DESIGN: In a cohort of 346 psychiatrically healthy subjects, we obtained diffusion tensor imaging, schizotypy using O-LIFE (Oxford-Liverpool Inventory of Feelings and Experiences), and polygenic risk scores (PRS) for schizophrenia risk and resilience to schizophrenia. Using FSL and TBSS (tract-based spatial statistics), we first analyzed the association between O-LIFE and fractional anisotropy (FA) for the anterior thalamic radiation, uncinate fascicle, and cingulum bundle, as well as moderation analyses with PRS scores.

RESULTS: O-LIFE dimensions were differentially associated with structural connectivity, in particular, negative schizotypy positively to right uncinate FA, positive schizotypy negatively to right cingulum and disorganized schizotypy negatively to left cingulum. In disorganized schizotypy the association was moderated by schizophrenia PRS.

CONCLUSIONS: Our results support a neurobiological continuum model of structural connectivity across psychosis proneness, emphasizing differential association with different schizotypy facets. Genetic schizophrenia risk, however, appears to impact only some of these associations, highlighting the need for further studies to understand the contribution of other genetic and/or environmental factors.

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

PMID: 40037820

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