Epigenetic Variation and its Determinants in Depression

描述（由申请人提供）：这项提案来自一位新的研究者，旨在确定抑郁症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度酒精和/或大麻使用的影响。该项目将利用现有的密切合作，在精神病学和遗传医学的团体之间，汇集了2个杰出的资源：一个非常大的和严格评估的家族性抑郁症的样本，从遗传学复发性早发性抑郁症（GENRED）研究，共同领导的博士。以及由Andrew Feinberg博士领导的常见疾病表观遗传学中心提供的表观遗传修饰研究的最先进方法。在这个提议中，基因启动子中的DNA甲基化，一个可以影响基因表达的关键表观遗传机制，将在抑郁症和对照组之间进行比较。同样，将在这些受试者中评估等位基因表达不均等（表观遗传变异的潜在指标）。前者将使用全血DNA，而后者将测试培养的淋巴细胞。对于两种试验，还将采用死后脑组织作为变异性初始筛选的一部分。将在297例GENRED病例和297例对照中检测血液来源和脑组织中变异性阳性的基因。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GENRED样本中报道的15 q25 -26连锁峰下的基因。生物信息学分析将评估这些基因启动子区中潜在的甲基化敏感性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含CpG二核苷酸序列优先用于研究。在抑郁受试者中发现表观遗传差异的情况下，将对相关基因进行基因分型，以检测基因型表观基因型相关性，并将现有的全基因组微卫星数据用于与表观基因型作为内表型的连锁。将测试酒精和大麻滥用和依赖诊断与表观基因型的相关性。还将使用回归模型探讨变量之间的相互作用。本申请中提出的新研究的结果应该阐明导致抑郁症易感性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.