Polygenic contributions to brain cortical measures, subcortical volumes and hippocampal subfields in first episode psychosis.

BACKGROUND

Psychosis is characterized by both genetic and neurostructural abnormalities. However, the mechanisms linking genetic risk to brain structural alterations remain unclear. This study investigates associations between polygenic risk scores (PRS) and brain structural measures in individuals experiencing a first-episode psychosis (FEP) and healthy controls (HC).

METHODS

A total of 241 participants (130 FEP, 111 HC, mean age = 24.8 years, 34.9% females) underwent structural magnetic resonance imaging (MRI) and genotyping. PRS for schizophrenia, educational attainment, brain cortical thickness, and surface area were computed using PRS continuous shrinkage (PRS-CS). MRI data provided measures of cortical thickness, surface area, subcortical volumes, and hippocampal subfields. Associations between PRS and brain measures were assessed using generalized linear models within each group.

RESULTS

FEP participants had significantly higher PRS for schizophrenia (p.adj = 1.56e-6) and lower PRS for educational attainment (p.adj = 0.006) compared to HC, but groups did not differ in neurostructural PRS. Neuroimaging revealed trend-level reductions in left hippocampal volume (p = 0.040, p.adj = 0.280) and significant reductions in specific hippocampal subfields in FEP. In PRS-brain structure analyses, significant associations were observed only in HC, while in FEP, educational attainment PRS showed nominal associations with multiple hippocampal subfields.

CONCLUSION

By incorporating polygenic scores for brain structural traits, our study shows that neurostructural genetic risk does not differ between FEP and HC, even as FEP participants exhibit significant reductions in specific hippocampal subfields. Genetic influences on brain structure in early psychosis appear subtle and region-specific, underscoring the complex interplay between distinct genetic domains and neurodevelopment in psychosis.