Epigenetics and disease: the role of DNA methylation in schizophrenia susceptibil

描述(申请人提供)：大多数精神疾病不是由单一基因突变引起的，而是涉及许多基因和分子信号控制下的细胞通路。最近的研究指出，复杂的表观遗传机制在基因核苷酸序列之上调节基因活性也可能参与其中。最被理解的表观遗传修饰机制是DNA甲基化。在这项全基因组研究中，我们将研究DNA甲基化在精神分裂症易感性中的作用。我们的研究包括全基因组的发现和复制阶段，以确定人类基因组中受表观遗传控制并与疾病易感性相关的CpG基因座，然后在大型精神分裂症队列中进行特定基因座的验证。我们识别与疾病相关的候选CpG基因座的系统方法还包括研究DNA甲基化的一般特征，如年龄、性别和遗传控制。通过对患者和对照组的多个大脑区域进行比较分析，全基因组范围的努力将提供一个独特的机会，来确定DNA甲基化在精神分裂症和其他精神疾病特征的易感性中所起的作用。公共卫生相关性：DNA和染色体结构的生化修饰提供了可遗传的信息，这些信息不在DNA序列本身中编码，但可能在疾病易感性中发挥作用。我们将筛选精神分裂症患者和未受影响的对照受试者的人类基因组，以确定这些与疾病有关的位置。这将有助于更好地了解精神分裂症的遗传基础。

DESCRIPTION (provided by applicant): Most psychiatric disorders are not due to mutations in a single gene but rather involve cellular pathways under control of many genes and molecular signals. Recent studies point to the fact that complex epigenetic mechanisms regulating gene activity 'above' the genetic nucleotide sequence may be involved as well. The best understood mechanism of epigenetic modification is DNA methylation. In this genome-wide study we will examine the role of DNA methylation in schizophrenia susceptibility. Our study consists of a genome-wide discovery and replication phase to identify CpG loci in the human genome that are under epigenetic control and involved in disease susceptibility, followed by locus-specific validation in large schizophrenia cohorts. Our systematic approach for identifying candidate CpG loci involved in disease also includes study of general features of DNA methylation such as age, gender and genetic controls. The genome-wide effort with comparative analyses of multiple brain regions of patients and controls will provide a unique opportunity to establish what role DNA methylation plays in vulnerability to develop schizophrenia and perhaps other psychiatric traits. Public Health Relevance: Biochemical modifications of DNA and chromosome structure provide heritable information that is not encoded in the DNA sequence itself, but is likely to play a role in disease susceptibility. We will screen the human genome of schizophrenia patients and unaffected control subjects in order to identify these sites involved in disease. This will lead to a better understanding of the genetic basis of schizophrenia.