The striatum, a core brain structure relevant for schizophrenia, exhibits heterogeneous volumetric changes in this illness. Due to this heterogeneity, its role in the risk of developing schizophrenia following exposure to environmental stress remains poorly understood. Using the putamen (a subnucleus of the striatum) as an indicator for convergent genetic risk of schizophrenia, 63 unaffected first-degree relatives of patients (22.08 ± 4.80 years) with schizophrenia (UFR-SZ) were stratified into two groups. Compared with healthy controls (HC; n = 59), voxel-based and brain-wide volumetric changes and their associations with stressful life events (SLE) were tested. These stratified associations were validated using two large population-based cohorts (the ABCD study; n = 1680, 11.92 ± 0.62 years; and UK Biobank, n = 20547, 55.38 ± 7.43 years). Transcriptomic analysis of brain tissues was used to identify the biological processes associated with the brain mediation effects on the SLE-psychosis relationship. The stratified UFR-SZ subgroup with smaller right putamen had a smaller volume in the left caudate when compared to HC; this caudate volume was associated with both a higher level of SLE and more psychotic symptoms. This caudate-SLE association was replicated in two independent large-scale cohorts, when individuals were stratified by both a higher polygenic burden for schizophrenia and smaller right putamen. In UFR-SZ, the caudate cluster mediated the relationship between SLE and more psychotic symptoms. This mediation was associated with the genes enriched in both glutamatergic synapses and response to oxidative stress. The stratified association between the striatum and stress highlights the differential vulnerability to stress, contributing to the complexity of the gene-by-environment etiology of schizophrenia.
© 2025. The Author(s).