Shishido Risa, Kunii Yasuto, Hino Mizuki, Izumi Ryuta, Nagaoka Atsuko, Hayashi Hideki, Kakita Akiyoshi, Tomita Hiroaki, Yabe Hirooki
Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Fukushima, Japan.
Department of Disaster Psychiatry, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan.
Front Psychiatry. 2023 Aug 22;14:1183696. doi: 10.3389/fpsyt.2023.1183696. eCollection 2023.
Schizophrenia (SZ) is a disorder diagnosed by specific symptoms and duration and is highly heterogeneous, clinically and pathologically. Although there are an increasing number of studies on the association between genetic and environmental factors in the development of SZ, the actual distribution of the population with different levels of influence of these factors has not yet been fully elucidated. In this study, we focused on stress as an environmental factor and stratified SZ based on the expression levels of stress-responsive molecules in the postmortem prefrontal cortex.
We selected the following stress-responsive molecules: interleukin (IL) -1β, IL-6, IL-10, tumor necrosis factor-α, interferon-γ, glucocorticoid receptor, brain-derived neurotrophic factor, synaptophysin, S100 calcium-binding protein B, superoxide dismutase, postsynaptic density protein 95, synuclein, apolipoprotein A1 (ApoA1), ApoA2, and solute carrier family 6 member 4. We performed RNA sequencing in the prefrontal gray matter of 25 SZ cases and 21 healthy controls and conducted a hierarchical cluster analysis of SZ based on the gene expression levels of stress-responsive molecules, which yielded two clusters. After assessing the validity of the clusters, they were designated as the high stress-response SZ group and the low stress-response SZ group, respectively. Ingenuity Pathway Analysis of differentially expressed genes (DEGs) between clusters was performed, and Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining was conducted on four cases each in the high and low stress-response SZ groups to validate DNA damage.
We found higher prevalence of family history of SZ in the low stress-response SZ group (0/3 vs. 5/4, = 0.04). Pathway analysis of DEGs between clusters showed the highest enrichment for DNA double-strand break repair. TUNEL staining showed a trend toward a lower percentage of TUNEL-positive cells in the high stress-response SZ group.
Our results suggest that there are subgroups of SZ with different degrees of stress impact. Furthermore, the pathophysiology of these subgroups may be associated with DNA damage repair. These results provide new insights into the interactions and heterogeneity between genetic and environmental factors.
精神分裂症（SZ）是一种根据特定症状和病程进行诊断的疾病，在临床和病理上具有高度异质性。尽管关于遗传和环境因素在SZ发病中的关联研究越来越多，但这些因素不同影响水平的人群实际分布情况尚未完全阐明。在本研究中，我们将压力作为环境因素，并根据死后前额叶皮质中应激反应分子的表达水平对SZ进行分层。
我们选择了以下应激反应分子：白细胞介素（IL）-1β、IL-6、IL-10、肿瘤坏死因子-α、干扰素-γ、糖皮质激素受体、脑源性神经营养因子、突触素、S100钙结合蛋白B、超氧化物歧化酶、突触后致密蛋白95、突触核蛋白、载脂蛋白A1（ApoA1）、ApoA2和溶质载体家族6成员4。我们对25例SZ患者和21例健康对照的前额叶灰质进行了RNA测序，并基于应激反应分子的基因表达水平对SZ进行了层次聚类分析，得到两个聚类。在评估聚类的有效性后，分别将它们指定为高应激反应SZ组和低应激反应SZ组。对聚类之间的差异表达基因（DEG）进行了 Ingenuity 通路分析，并对高应激反应SZ组和低应激反应SZ组各4例进行了末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）染色以验证DNA损伤。
我们发现低应激反应SZ组中SZ家族史的患病率更高（0/3对5/4，P = 0.04）。聚类之间DEG的通路分析显示DNA双链断裂修复的富集程度最高。TUNEL染色显示高应激反应SZ组中TUNEL阳性细胞百分比有降低的趋势。
我们的结果表明，存在受压力影响程度不同的SZ亚组。此外，这些亚组的病理生理学可能与DNA损伤修复有关。这些结果为遗传和环境因素之间的相互作用和异质性提供了新的见解。
