Epigenetic Variation and its Determinants in Depression

描述(由申请人提供)：这项由一位新的研究人员提出的建议，旨在确定抑郁症受试者和对照受试者之间的DNA表观遗传修饰是否不同，以及相关的表观遗传标记是否受到遗传变异和重酒和/或大麻使用的影响。该项目将利用精神病学和遗传医学小组之间现有的密切合作，汇集了两个杰出的资源：由J.Raymond DePaulo博士共同领导的复发性早发性抑郁症(GENRED)研究的一个非常大的和经过严格评估的家族性重度抑郁症样本，以及由Andrew Feinberg博士领导的常见疾病表观遗传学中心提供的最先进的表观遗传修饰研究方法。在这项建议中，基因启动子中的DNA甲基化是影响基因表达的关键表观遗传机制，将在抑郁症患者和对照组之间进行比较。类似地，在这些受试者中将评估等位基因表达不平等，这是表观遗传变异的一个潜在指标。前者将使用全血DNA，而后者将测试培养的淋巴细胞。在这两种检测中，死后脑组织也将被用作变异性的初始筛查的一部分。在血液和脑组织中都呈变异性阳性的基因将在297个基因病例和297个对照中进行测试。待分析的基因包括14个功能候选基因和43个位置候选基因，后者是最近在基因组样本中报道的15q25-26连锁高峰下的基因。生物信息学分析将评估这些基因启动子区域中潜在的甲基化敏感转录因子结合位点和糖皮质激素调节元件，以确保这些功能相关的CpG二核苷酸序列被优先研究。在抑郁症受试者中发现表观遗传差异的情况下，将在相关基因内进行基因分型以测试基因型表观类型关联，并将现有的全基因组微卫星数据用于与表观类型作为内表型的连锁。酒精和大麻滥用和依赖诊断将测试它们与表观类型的关联。变量之间的相互作用也将使用回归模型进行探索。在这项申请中提出的新研究的结果应该有助于阐明导致易患抑郁症的表观遗传机制和基因-环境相互作用。

DESCRIPTION (provided by applicant): This proposal, from a new investigator, aims to determine whether epigenetic modification of DNA differs between depressed and control subjects, and whether relevant epigenetic marks are influenced by genetic variation and by heavy alcohol and/or cannabis use. This project will take advantage of an existing close collaboration, between groups within psychiatry and genetic medicine, that brings together 2 outstanding resources: a very large and rigorously assessed sample of familial major depression, from the Genetics of Recurrent Early Onset Depression (GENRED) study, co-led by Dr. J. Raymond DePaulo, Jr., and the state of-the-art methods for the study of epigenetic modification available through the Center for the Epigenetics of Common Disease, led by Dr. Andrew Feinberg. In this proposal, DNA methylation in gene promoters, a key epigenetic mechanism that can influence gene expression, will be compared between depressed and control subjects. Similarly, unequal allelic expression, a potential indicator of epigenetic variation, will be assessed in these subjects. The former assay will use whole blood DNA, while the latter will test cultured lymphocytes. For both assays, post-mortem brain tissue will also be employed as part of an initial screen for variability. Genes that are positive for variability in both blood-derived and brain tissues will be tested in 297 GENRED cases and 297 controls. The genes to be analyzed include 14 functional candidates and 43 positional candidates, the latter being those under a 15q25-26 linkage peak recently reported in the GENRED sample. Bioinformatic analysis will assess potentially methylation-sensitive transcription factor binding sites and glucocortocoid modulatory elements in the promoter regions of these genes, to ensure that these functionally relevant CpG dinucleotide-containing sequences are prioritized for study. Where epigenetic differences are found in depressed subjects, genotyping within implicated genes will be performed to test for genotype epigenotype association, and existing genome-wide microsatellite data will be used for linkage with epigenotype as an endophenotype. Alcohol and cannabis abuse and dependence diagnoses will be tested for their association with epigenotypes. Interactions among variables will also be explored using regression models. Results from the novel studies proposed in this application should shed light on the epigenetic mechanisms and gene-environment interactions that result in vulnerability to depression.