Subtypes of schizophrenia identified by multi-omic measures associated with dysregulated immune function
Subtypes of schizophrenia identified by multi-omic measures associated with dysregulated immune function
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通过多组学措施鉴定与免疫功能失调相关的精神分裂症亚型
DOI：
10.1038/s41380-021-01308-6
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发表时间：
2021
影响因子：
11
通讯作者：
Lui Su
中科院分区：
文献类型：
--
作者：
Luo Chunyan;Pi XueNan;Hu Na;Wang Xiao;Xiao Yuan;Li Siyi;Sweeney John A.;Bishop Jeffrey R.;Gong Qiyong;Xie Dan;Lui Su
表观遗传修饰是精神分裂症患者表型异质性的合理分子来源。目前的研究调查了精神分裂症的生物异质性，使用外周表观遗传特征来描述疾病亚型，独立于其现象学表现。我们应用表观基因组全谱与DNA甲基化阵列从63名精神分裂症患者和59名健康对照的血液样本。进行非负矩阵分解（NMF）和k均值聚类以鉴定DNA甲基化相关的患者亚型。通过评估T细胞受体（TCR）库的概况来测试分区的有效性。评估了与脑结构和临床测量相关的已鉴定亚型的独特性。在患者中鉴定了两种不同的DNA甲基化模式。与对照组相比，一种亚型（60.3%的患者）的甲基化水平和细胞组成变化相对有限，而第二种亚型（39.7%的患者）在富含免疫细胞活性的基因中表现出广泛的甲基化水平变化，以及中性粒细胞比例较高和淋巴细胞比例较低。两种患者亚型的区分通过TCR库来验证，TCR库基于DNA甲基化谱来确定分区。与其他亚型相比，具有广泛甲基化修饰的亚型具有更高的症状严重程度，在认知测量中表现更差，并且显示出白色物质束的分数各向异性和灰质增厚的证据的更大降低。鉴定具有独特分子、大脑和临床特征的精神分裂症的不同亚型，为精神分裂症综合征提供了一种新的分类，具有指导个体化治疗的潜力。
Epigenetic modifications are plausible molecular sources of phenotypic heterogeneity across schizophrenia patients. The current study investigated biological heterogeneity in schizophrenia using peripheral epigenetic profiles to delineate illness subtypes independent of their phenomenological manifestations. We applied epigenome-wide profiling with a DNA methylation array from blood samples of 63 schizophrenia patients and 59 healthy controls. Non-negative matrix factorization (NMF) and k-means clustering were performed to identify DNA methylation-related patient subtypes. The validity of the partition was tested by assessing the profile of the T cell receptor (TCR) repertoires. The uniqueness of the identified subtypes in relation to brain structural and clinical measures were evaluated. Two distinct patterns of DNA methylation profiles were identified in patients. One subtype (60.3% of patients) showed relatively limited changes in methylation levels and cell composition compared to controls, while a second subtype (39.7% of patients) exhibited widespread methylation level alterations among genes enriched in immune cell activity, as well as a higher proportion of neutrophils and lower proportion of lymphocytes. Differentiation of the two patient subtypes was validated by TCR repertoires, which paralleled the partition based on DNA methylation profiles. The subtype with widespread methylation modifications had higher symptom severity, performed worse on cognitive measures, and displayed greater reductions in fractional anisotropy of white matter tracts and evidence of gray matter thickening compared to the other subtype. Identification of a distinct subtype of schizophrenia with unique molecular, cerebral, and clinical features provide a novel parcellation of the schizophrenia syndrome with potential to guide development of individualized therapeutics.