Dong Huixi, Luo Tao, Yang Cheng, Liu Mengqi, Shen Yidong, Hao Wei
Mental Health Center of Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
Schizophrenia (Heidelb). 2024 Oct 9;10(1):91. doi: 10.1038/s41537-024-00506-9.
Methamphetamine use can produce psychotic symptoms almost indistinguishable from schizophrenia (SCZ). Variation in DNA methylation may be closely implicated in the etiology and longitudinal development of psychiatric disorders. However, the relationship between psychotic symptoms, functional disability, and DNA methylation is still unclear. This study consists of three periods: discovery, validation, and follow-up. In the discovery stage, we employed genome-wide DNA methylation profiling (Illumina 450K) in peripheral blood mononuclear cells to test whether DNA methylation associates with psychotic symptoms and function state in representative SCZ and methamphetamine-induced psychotic disorder (MIP) patients. Then, we found seven differentially methylated regions/genes (DMRs, in UBA6, APOL3, KIF17, MLLT3, GRM8, CSNK1E, SETDB1) overlapping with genetic variants reported in previous studies of psychosis. In the validation stage, we compared the above-mentioned seven genes by MethLight qPCR method in Chinese Han males (N = 109 SCZ patients, N = 99 methamphetamine use disorder with MIP patients, N = 150 methamphetamine use disorder without MIP patients, N = 282 normal controls, age range: 18-50 years). GRM8 showed robustly altered methylation, which has passed rigorous filtration in subsequent validation, suggesting a remarkable contribution to SCZ and MIP. In addition, hypermethylation of GRM8 showed a significant association with the total scores of the Positive Negative Syndrome Scale and WHO disability assessment schedule II in both baseline and follow-up periods. Our findings suggest that increased CpG methylation in the promoter of GRM8 is a potential candidate epigenetic biomarker of psychotic symptoms in transdiagnostic samples of SCZ and MIP.
使用甲基苯丙胺可产生几乎与精神分裂症（SCZ）无法区分的精神病性症状。DNA甲基化的变化可能与精神疾病的病因和纵向发展密切相关。然而，精神病性症状、功能残疾与DNA甲基化之间的关系仍不清楚。本研究包括三个阶段：发现、验证和随访。在发现阶段，我们对外周血单个核细胞进行全基因组DNA甲基化分析（Illumina 450K），以检测DNA甲基化是否与代表性的SCZ和甲基苯丙胺所致精神病性障碍（MIP）患者的精神病性症状和功能状态相关。然后，我们发现了七个差异甲基化区域/基因（DMRs，位于UBA6、APOL3、KIF17、MLLT3、GRM8、CSNK1E、SETDB1中），这些区域/基因与先前精神病研究中报道的基因变异重叠。在验证阶段，我们采用MethLight qPCR方法对中国汉族男性（N = 109例SCZ患者，N = 99例患有MIP的甲基苯丙胺使用障碍患者，N = 150例无MIP的甲基苯丙胺使用障碍患者，N = 282例正常对照，年龄范围：18 - 50岁）中的上述七个基因进行了比较。GRM8显示出甲基化的显著改变，并在后续验证中通过了严格筛选，表明其对SCZ和MIP有显著贡献。此外，GRM8的高甲基化在基线期和随访期均与阳性和阴性症状量表总分以及世界卫生组织残疾评估表II显著相关。我们的研究结果表明，GRM8启动子区域CpG甲基化增加是SCZ和MIP跨诊断样本中精神病性症状的潜在表观遗传生物标志物。
