COMT 甲基化与 ADHD 患儿治疗反应的关系。
Association between COMT methylation and response to treatment in children with ADHD.
机构信息
Douglas Mental Health University Institute, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Institute of Psychiatry and Neurosciences of Paris, Paris, France; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
出版信息
J Psychiatr Res. 2021 Mar;135:86-93. doi: 10.1016/j.jpsychires.2021.01.008. Epub 2021 Jan 7.
BACKGROUND
COMT had been considered a promising candidate gene in pharmacogenetic studies in ADHD; yet the findings from these studies have been inconsistent. Part of these inconsistencies could be related to epigenetic mechanisms (including DNA methylation). Here we investigated the role of genetic variants of the COMT gene on the methylation levels of CpG sites in the same gene and explored the effect of methylation on methylphenidate (MPH) and placebo (PBO) response in children with ADHD.
METHODS
Two hundred and thirty children with ADHD (6-12 years) participated in a randomized, double-blind, placebo-controlled crossover trial with MPH. Univariate analysis was performed to examine the associations between genotypes in the COMT gene and DNA methylation in the same genetic loci. Association between the DNA methylation of 11 CpG sites and PBO/MPH responses were then assessed using spearman's correlation analysis in 212 children. Multiple linear regression analyses were performed to test the interaction between these factors while accounting for sex.
RESULTS
Associations were observed between specific genetic variants and methylation level of cg20709110. Homozygous genotypes of GG (rs6269), CC (rs4633), GG (rs4818), Val/Val (rs4680) and the haplotype (ACCVal/GCGVal) were significantly associated with higher level of methylation. This CpG showed a significant correlation with placebo response (r = -0.15, P = 0.045) according to the teachers' evaluation, and a close-to significance correlation with response to MPH according to parents' evaluation (r = -0.134, p = 0.051). Regression analysis showed that in the model including rs4818, sex and DNA methylation of cg20709110 contributed significantly to treatment response.
CONCLUSIONS
These preliminary results could provide evidence for the effect of genetic variations on methylation level and the involvement of the epigenetic variation of COMT loci in modulating the response to treatment in ADHD.
TRIAL REGISTRATION
clinicaltrials.gov, number NCT00483106.
背景
COMT 被认为是 ADHD 药物遗传学研究中有前途的候选基因；然而，这些研究的结果并不一致。这些不一致的部分可能与表观遗传机制（包括 DNA 甲基化）有关。在这里，我们研究了 COMT 基因的遗传变异与同一基因中 CpG 位点的甲基化水平之间的关系，并探讨了甲基化对 ADHD 儿童接受哌醋甲酯（MPH）和安慰剂（PBO）治疗反应的影响。
方法
230 名 ADHD 儿童（6-12 岁）参加了一项随机、双盲、安慰剂对照的哌醋甲酯交叉试验。采用单变量分析方法，研究 COMT 基因中的基因型与同一遗传位点的 DNA 甲基化之间的关系。然后，在 212 名儿童中，采用 Spearman 相关分析评估 11 个 CpG 位点的 DNA 甲基化与 PBO/MPH 反应之间的相关性。进行多元线性回归分析，以测试这些因素之间的相互作用，同时考虑性别因素。
结果
观察到特定遗传变异与 cg20709110 甲基化水平之间存在关联。GG(rs6269)、CC(rs4633)、GG(rs4818)、Val/Val(rs4680)和单倍型（ACCVal/GCGVal）的纯合基因型与较高的甲基化水平显著相关。根据教师评估，该 CpG 与安慰剂反应呈显著负相关（r=-0.15，P=0.045），根据父母评估与 MPH 反应呈接近显著负相关（r=-0.134，P=0.051）。回归分析表明，在包括 rs4818、性别和 cg20709110 甲基化的模型中，治疗反应有显著贡献。
结论
这些初步结果为遗传变异对甲基化水平的影响以及 COMT 基因座的表观遗传变异在调节 ADHD 治疗反应中的作用提供了证据。
试验注册
clinicaltrials.gov，编号 NCT00483106。
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