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

项目2：5HTTLPR基因型和其他相互作用基因的影响

基本信息

批准号：
8059840
负责人：
MYRNA M WEISSMAN
金额：
$ 19.73万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8059840
关键词：
Address Adolescence Adult Basic Science Biological Markers Candidate Disease Gene Clinical Clinical Data Cohort Studies DNA Data Data Set Diagnosis Diagnostic Electroencephalography Epistatic Gene Family Family member Functional Imaging Generations Genes Genetic Genetic Polymorphism Genetic Variation Genomics Genotype HTR2A gene Heritability Individual Lead Link Magnetic Resonance Imaging Major Depressive Disorder Mediating Mental Depression Methaqualone National Institute of Mental Health Onset of illness Phenotype Population Publishing Recording of previous events Recurrence Risk Sampling Serotonin Testing Time Variant alternative treatment base blind brain morphology clinical phenotype cohort design disability disorder control early onset follow-up gene environment interaction genetic association high risk investigator training repository serotonin transporter

项目摘要

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.

重度抑郁症（MDD）很常见，首次发作。通常在青春期，重新出现到成年后，这是残疾范围内的主要原因，遗传力PF 31-50％。人们普遍认为，MDD可能涉及某些个体中5-羟色胺自然或实验性改变的脆弱性。我们的整体贡献将是了解如何通过利用具有MDD高/低风险的独特的3代家庭来改变与5-羟色调相关的基因和神经记录的变化可以改变MDD的风险。在25年内，该队列已被预期最多五次。所有评估均对以前的临床病史看不见，诊断其他家庭成员，并包括广泛的临床数据和生物标记。该设计使我们能够在疾病发作之前研究高风险人群，从而从补偿机制中解散了因果关系。我们拥有有关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的EEG 受试者，导致最大的具有生物标记的MDD家族样本。我们有很强的临床和MRI发现。我们建议进一步研究此队列。我们将收集150名受试者的DNA，首先针对已经具有MRI和/或脑电图数据的受试者，但不能DNA，因此，我们可以更全面地解决与伊素蛋白相关的遗传变异如何导致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。我们将扩大多态性测试新候选者的数量，并将测试基因通过环境相互作用的基因（上皮）和基因。我们将进行基于基因的基因分型，以促进该样本中收集的诊断，脑电图和MRI表型的基于家庭的遗传关联测试。此外，我们有3000多个具有MDD的受试者和大约3000个对照组，这些对照已被基因分型和表征，我们将使用它们来跟进遗传发现。 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 MDD和对照的遗传样本。我们的发现将用于指导和产生其他项目的假设，还将测试其他项目的发现。我们将为这些联系中的人群，临床和基础科学的翻译联系以及研究人员的培训做出贡献。