Abstract
Schizophrenia (SCZ) is a severe neurodevelopmental mental disorder with age-dependent onset, and healthy siblings of SCZ patients are a pivotal cohort for exploring genetic susceptibility. This study aimed to characterize age-differentiated gray matter volume (GMV) patterns in high-risk and non-high-risk age siblings of SCZ patients via structural magnetic resonance imaging (sMRI), and clarify the regulatory role of age in neurostructural correlates of genetic susceptibility. A total of 31 SCZ patients, 62 healthy siblings (divided into age-sensitive window siblings [ASW-SIB, 18-35 years, n=31] and post-age-sensitive window siblings [PASW-SIB, 36-45 years, n=31]), and 31 healthy controls (HCs) were enrolled. Patients with schizophrenia (SCZ, n=31) and healthy controls (HCs, n=31) were age-matched to the sibling cohort (overall mean age: 30.55 ± 7.84 years) but not further stratified by age, as the core aim was to compare age-specific sibling subgroups with non-stratified reference groups, however, post-hoc pairwise comparisons (Bonferroni-corrected) showed that PASW-SIB were significantly older than both SCZ (p < 0.001) and HCs (p < 0.001). sMRI data were processed using voxel-based morphometry (VBM8), and inter-group GMV comparisons were performed with one-way ANOVA and two-sample t-tests. Results showed no significant differences in demographic characteristics among the three groups (all p>0.05). One-way ANOVA revealed significant main effects of group on GMV in brain regions including the caudate nucleus, pallidum, insula, parahippocampal gyrus, and precuneus (F = 1.28-1.96, all p<0.01). Pairwise comparisons indicated that compared with HCs, PASW-SIB exhibited significantly increased GMV in the caudate nucleus, pallidum, and insula (all p<0.05, FDR-corrected), while ASW-SIB only showed reduced GMV in the parahippocampal gyrus and precuneus (all p<0.05, FDR-corrected). In contrast, SCZ patients exhibited reduced GMV in multiple regions (inferior temporal gyrus, superior frontal gyrus, postcentral gyrus, and insula) compared to HCs (all p < 0.05, FDR-corrected). No significant correlations were found between GMV and clinical symptoms (PANSS scores) or disease duration in SCZ patients (all p>0.05). These findings suggest age-associated GMV differences in healthy siblings of SCZ patients: PASW-SIB show widespread GMV alterations in the basal ganglia and insula, while ASW-SIB exhibit localized GMV differences in the default mode network. The age-specific neurostructural patterns are consistent with potential risk-related brain phenotypes for SCZ, which may provide imaging targets for future studies of early risk stratification and intervention in high-risk populations.