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

重度抑郁障碍(MDD)很常见，通常在青春期发病，成年期反复发作，是全球残疾的主要原因，遗传率为31%-50%。人们普遍认为，MDD可能涉及某些个体对5-羟色胺自然或实验变化的易感性。我们的整体 其贡献将是了解与5-羟色胺能紧张素相关的基因和神经回路的变异如何通过利用MDD高/低风险的三代家庭的独特队列来改变MDD的风险。在过去的25年里，这一队列被前瞻性地跟踪了多达5次。所有的评估都是在不考虑以前的临床病史、其他家庭成员的诊断的情况下进行的，并且包括大量的临床数据和生物标志物。这一设计使我们能够在疾病发生之前研究高危人群，从而从补偿机制中分离出因果效应。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，234名受试者的脑电 受试者，导致了拥有生物标记的MDD家庭的最大可用样本。我们有很强的已发表的临床和核磁共振结果。我们建议对这一队列进行进一步研究。我们将收集另外150名受试者的DNA，首先是那些已经有MRI和/或EEG数据但没有DNA的受试者，所以 我们可以更全面地研究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-羟色胺基因与MDD之间的关系。我们将扩大多态的数量来测试新的候选基因，并将测试基因 通过基因(上位性)和基因与环境的相互作用。我们将进行有重点的基于基因的基因分型，以促进基于家族的基因检测与本样本中收集的诊断、EEG和MRI表型的遗传关联。此外，我们有超过3000个MDD受试者样本和大约3000个对照样本，他们已经进行了基因分型和特征，我们将使用他们来跟进基因发现。有四个目标：(1)收集150个新的3代样本并分离基因组DNA，(2)在3代样本中对69个DNA变异进行基因分型，(3)用MRI和EEG检查患有MDD和其他相关临床表型的DNA变异，以及(4)复制现有大样本中前10%的发现 MDD和对照的遗传样本。我们的发现将用于指导和生成来自其他项目的假设，并将测试来自其他项目的结果。我们将促进人口、临床和基础科学的翻译联系，并在这些联系中培训研究人员。

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.