2026 ECNP Congress

PS01-1151

Polygenic influences on brain structure in youth across the psychosis-spectrum

Irene Martínez Serrano — C. Núñez, À. G Segura, M. Ortuño, D. Ilzarbe, P. Camprodon Boadas, A. Fortea, E. De La Serna, S. Mas, I. Baeza, J. Castro Fornieles, G. Sugranyes · Fundació Clínic per a la Recerca Biomèdica – August Pi i Sunyer Biomedical Research Institute IDIBAPS, Department of Medicine- Faculty of Medicine and Health Sciences- Institute of Neuroscience- University of Barcelona, Barcelona, Spain

2026 ECNP Congress

Genetic variation contributes to brain structural organization and development [1], yet the extent to which polygenic scores (PGS) for psychiatric disorders shape these processes during the early stages of psychosis remains unclear. While PGS provide a useful estimate of overall genetic liability, their influence on neuroanatomical variation during critical neurodevelopmental windows is not yet fully delineated [2]. In particular, childhood and adolescence represent sensitive periods marked by dynamic cortical remodeling, during which genetic liability may interact with ongoing maturational processes to influence trajectories toward psychosis [3]. In this study, we investigated the association between PGS for psychiatric disorders and measures of brain structure at cross-section in 208 psychosis‑spectrum youth (at increased clinical or familial risk for psychosis or with first-episode psychosis) and 115 healthy controls (HC), aged 8-18 years. PGSs for schizophrenia, bipolar disorder, major depressive disorder, and attention-deficit/hyperactivity disorder (ADHD) were computed using PRS-CS, based on genome-wide summary statistics from the Psychiatric Genomics Consortium. High-resolution T1-weighted magnetic resonance imaging data were processed with the CAT12 toolbox to derive cortical and subcortical gray matter volumes, cortical thickness, and gyrification indices. Linear regression models were implemented to examine both main effects of PGS and PGS-by-group interactions, adjusting for relevant covariates including age, quadratic age effects, sex, scanner, intracranial volume, and four principal genetic ancestry components. Higher PGS for schizophrenia was associated with greater cortical thickness across widespread regions, including frontal, parietal, temporal, and cingulate cortices, in the full sample. In contrast, PGS for bipolar disorder showed significant PGS-by-group interactions for gray matter volume, particularly in temporal and cingulate regions, with positive associations in psychosis-spectrum youth and inverse associations in HC. Similarly, PGS for ADHD showed significant PGS-by-group interactions for cortical thickness. In psychosis-spectrum youth, higher PGS for ADHD was associated with reduced cortical thickness in frontal, parietal, and temporal regions, whereas the opposite pattern was observed in HC. In summary, in our sample, PGS for schizophrenia was related to widespread cortical variation, whereas PGS for bipolar disorder and PGS for ADHD showed group‑specific effects, suggesting distinct neurodevelopmental pathways in psychosis‑spectrum youth. These findings are consistent with evidence suggesting that both shared and disorder-specific genetic factors contribute to heterogeneous neurobiological trajectories within the psychosis spectrum [4]. Such variability may reflect alterations in normative neurodevelopmental processes, including synaptic pruning during adolescence. Integrating polygenic and neuroimaging approaches may help elucidate neurodevelopmental mechanisms underlying vulnerability to psychosis. Ultimately, this approach may contribute to the identification of biologically informed markers that refine early detection strategies and support the development of targeted interventions during critical developmental windows.

This study has been funded by Instituto de Salud Carlos III (FIS PI11/1349, PI15/0444, PI18/0242, PI18/00976, PI20/00654, PI21/00330, PI21/0391, PI21/00519), co-funded by the European Union, the Alicia Koplowitz Foundation and by the project FORT23/00002 through the “Programa FORTALECE del Ministerio de Ciencia, Innovación y Universidades”.

References

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