Department of Genetics, Stellenbosch University, Stellenbosch 7600, South Africa.
Department of Psychiatry, Stellenbosch University, Tygerberg 7505, South Africa.
Prog Neuropsychopharmacol Biol Psychiatry. 2018 Feb 2;81:38-49. doi: 10.1016/j.pnpbp.2017.10.004. Epub 2017 Oct 7.
Antipsychotic response in schizophrenia is a complex, multifactorial trait influenced by pharmacogenetic factors. With genetic studies thus far providing little biological insight or clinical utility, the field of pharmacoepigenomics has emerged to tackle the so-called "missing heritability" of drug response in disease. Research on psychiatric disorders has only recently started to assess the link between epigenetic alterations and treatment outcomes. DNA methylation, the best characterised epigenetic mechanism to date, is discussed here in the context of schizophrenia and antipsychotic treatment outcomes. The majority of published studies have assessed the influence of antipsychotics on methylation levels in specific neurotransmitter-associated candidate genes or at the genome-wide level. While these studies illustrate the epigenetic modifications associated with antipsychotics, very few have assessed clinical outcomes and the potential of differential DNA methylation profiles as predictors of antipsychotic response. Results from other psychiatric disorder studies, such as depression and bipolar disorder, provide insight into what may be achieved by schizophrenia pharmacoepigenomics. Other aspects that should be addressed in future research include methodological challenges, such as tissue specificity, and the influence of genetic variation on differential methylation patterns.
抗精神病药物治疗精神分裂症的反应是一种复杂的、多因素的特征，受遗传药理学因素的影响。由于迄今为止的遗传研究几乎没有提供生物学见解或临床实用性，因此出现了药物基因组学领域来解决药物反应所谓的“遗传缺失”问题。精神疾病的研究最近才开始评估表观遗传改变与治疗结果之间的联系。本文讨论了迄今为止研究得最好的表观遗传机制——DNA 甲基化，在精神分裂症和抗精神病药物治疗结果中的作用。大多数已发表的研究评估了抗精神病药物对特定神经递质相关候选基因或全基因组水平上的甲基化水平的影响。虽然这些研究说明了与抗精神病药物相关的表观遗传修饰，但很少有研究评估临床结果和差异 DNA 甲基化图谱作为抗精神病药物反应预测因子的潜力。来自其他精神障碍研究（如抑郁症和双相情感障碍）的结果为精神分裂症的药物基因组学可能取得的成就提供了一些见解。未来研究中还应解决其他方面的问题，包括组织特异性等方法学挑战，以及遗传变异对差异甲基化模式的影响。
