Ma Xiaoqian, Feng Nana, Palaniyappan Lena, Cao Luolong, Gu Zixin, Kang Jujiao, Yuan Liu, Ouyang Lijun, Wang Yujue, Li Chunwang, Jin Ke, Chen Xiaogang, Feng Jianfeng, He Ying, Luo Qiang
Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
China National Technology Institute on Mental Disorders, Changsha, Hunan, China.
Transl Psychiatry. 2025 Jan 22;15(1):18. doi: 10.1038/s41398-025-03237-2.
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.
纹状体是与精神分裂症相关的核心脑结构，在该疾病中表现出体积的异质性变化。由于这种异质性，其在暴露于环境压力后发生精神分裂症风险中的作用仍知之甚少。以壳核（纹状体的一个亚核）作为精神分裂症聚合遗传风险的指标，将63名精神分裂症患者（UFR-SZ）的未患病一级亲属（22.08±4.80岁）分为两组。与健康对照（HC；n = 59）相比，测试了基于体素的全脑体积变化及其与应激性生活事件（SLE）的关联。使用两个基于大人群的队列（ABCD研究；n = 1680，11.92±0.62岁；和英国生物银行，n = 20547，55.38±7.43岁）对这些分层关联进行了验证。对脑组织进行转录组分析，以确定与大脑对SLE-精神病关系的中介作用相关的生物学过程。与HC相比，右侧壳核较小的分层UFR-SZ亚组左侧尾状核体积较小；该尾状核体积与更高水平的SLE和更多精神病性症状均相关。当根据精神分裂症的更高多基因负担和较小的右侧壳核将个体分层时，这种尾状核-SLE关联在两个独立的大规模队列中得到了重复。在UFR-SZ中，尾状核簇介导了SLE与更多精神病性症状之间的关系。这种中介作用与谷氨酸能突触和氧化应激反应中富集的基因有关。纹状体与压力之间的分层关联突出了对应激的不同易感性，这导致了精神分裂症基因-环境病因的复杂性。
