Project 2: Effects of 5HTTLPR Genotype and Other Interacting Genes

重性抑郁症（MDD）是一种常见的疾病，通常在青春期首次发病，成年后复发，是世界范围内残疾的主要原因，遗传率为31- 50%。人们普遍认为，MDD可能涉及某些个体对5-羟色胺的自然或实验性改变的脆弱性。我们的整体 本研究的贡献将是通过利用MDD高/低风险的3代家族的独特队列，了解与多巴胺能紧张相关的基因和神经回路的变化如何改变MDD的风险。该队列在25年内进行了长达5次的前瞻性随访。所有评估均对既往临床病史、其他家族成员的诊断设盲，并包括广泛的临床数据和生物标志物。这种设计使我们能够在发病前研究高危人群，从而从补偿机制中解开因果效应。我们有900多名受试者的临床数据，307名受试者的DNA，216名受试者的结构/功能图像，以及234名受试者的EEG 受试者，导致最大的可用样本的家庭与MDD谁有生物标志物。我们已经发表了强有力的临床和MRI结果。我们建议进一步研究这一队列。我们将收集另外150名受试者的DNA，首先针对已经有MRI和/或EEG数据但没有DNA的受试者， 我们可以更全面地解决异羟色胺相关的遗传变异如何导致大脑形态或功能的变化，以及这些变化是否可能介导5-羟色胺基因和MDD之间的关系。我们将扩大多态性的数量，以测试新的候选人，并将测试基因 基因（上位性）和基因与环境的相互作用。我们将进行集中的基于基因的基因分型，以促进对该样本中收集的诊断、EEG和MRI表型进行基于家族的遗传相关性检测。此外，我们有超过3000例MDD受试者样本和约3000例对照样本，这些样本已进行了基因分型和特征分析，我们将使用这些样本来随访遗传学发现。有四个目标：（1）收集150个新的3代样本并分离基因组DNA，（2）对3代样本中的69个DNA变异进行基因分型，（3）用MDD和其他相关临床表型、MRI和EEG表型检查DNA变异，以及（4）复制可用的大样本中前10%的发现。 MDD和对照组的基因样本。我们的研究结果将用于指导和产生其他项目的假设，也将测试其他项目的研究结果。我们将为人口，临床和基础科学的翻译联系以及这些联系中的研究人员培训做出贡献。

Major depressive disorder (MDD) is common, with first onset.often in adolescence, recurrent into adulthood, a leading cause of disability woridwide, with a heritability pf 31-50%. It is widely accepted that MDD may involve a vulnerability to natural or experimental alterations in serotonin in certain individuals. Our overall contribution will be to understand how variation in genes and neurocircuitry related to serotonergic tone can modify the risk for MDD by taking advantage of a unique cohort of 3 generations of families at high/low risk for MDD. The cohort has been followed prospectively up to five times over 25 years. All assessments have been conducted blind to previous clinical history, diagnoses of other family members, and include extensive clinical data and biological markers. The design has allowed us to study high-risk populations prior to onset of illness, and thereby disentangle causal effects from compensatory mechanisms. We have clinical data on over 900 subjects, DNA on 307 subjects, structural/functional images on 216 subjects, and EEG on 234 subjects, resulting in the largest available sample of families with MDD who have biological markers. We have strong published clinical and MRI findings. We propose to further study this cohort. We will collect DNA on 150 additional subjects, first targeting subjects who already have MRI and/or EEG data, but not DNA, so that we can more comprehensively address how iserotonin-related genetic variation may lead to changes in brain morphology or function, and whether these changes might mediate the relationship between serotonin genes and MDD. We will expand the number of polymorphisms to test new candidates, and will test for gene by gene (epistatic) and gene by environment interactions. We will conduct focused gene-based genotyping in order to facilitate family-based tests of genetic association to the diagnostic, EEG, and MRI phenotypes collected in this sample. Additionally, we have over 3000 samples of subjects with MDD and about 3000 controls who have been genotyped and characterized whom we will use to follow up genetic findings. There are 4 aims: (1) To collect 150 new 3-generation samples and isolate genomic DNA, (2) to genotype 69 DNA variants in the 3-generation samples, (3) to examine the DNA variants with MDD and other related clinical phenotypes, with MRI, and with EEG phenotypes, and (4) to replicate the top 10% findings in available large genetic samples of MDD and controls. Our findings will be used to guide and generate hypotheses from the other Projects and will also test findings from the other Projects. We will contribute to the translational linking of population, clinical, and basic science and training of investigators in these links.