Genetic Linkage Studies in Bipolar Disorder Families

双相情感障碍家庭的遗传连锁研究

基本信息

批准号：
7434025
负责人：
Elliot S Gershon
金额：
$ 37.25万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-15 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7434025
关键词：
13q 13q33 18q 22q 22q12 8q24 Affect Bioinformatics Bipolar Disorder Borderline Personality Disorder Brain-Derived Neurotrophic Factor Bronchopulmonary Dysplasia Candidate Disease Gene Cell Line Chicago Chromosomes Classification Clinical Collaborations Collection Comorbidity Complex Core Facility DNA Data Data Linkages Data Set Disease Factor Analysis Family Family member Frequencies Funding Genes Genetic Genetic Heterogeneity Genome Scan Genotype Goals Haplotypes Individual Inherited Investigation Laboratories Logistics Methods Microsatellite Repeats Mitochondrial DNA Mood Disorders Mutation Analysis National Institute of Mental Health Nuclear Family Panic Disorder Parents Phenotype Population Potassium Hydroxide Range Reporting Research Research Personnel Resources SNP genotyping Sampling Scanning Siblings Signal Transduction Site Standards of Weights and Measures Suicide attempt Susceptibility Gene Symptoms System Testing Universities Variant base case control data management density design follow-up genetic linkage genetic linkage analysis genetic pedigree genome-wide linkage imprint improved interest lymphoblastoid cell line novel proband programs web based interface

项目摘要

DESCRIPTION (provided by applicant): This project is a continuation of a 3-site collaboration-- between investigators at Johns Hopkins, the University of Chicago, and the National Institute of Mental Health--that has developed a bipolar disorder family resource that has proven to be uniquely valuable in testing clinically based hypotheses about the genetic heterogeneity of the illness. The findings developed from this project so far include the first systematic studies of the distribution and genetic salience of the bipolar II phenotype and of psychotic bipolar disorder. This project has also first identified important candidate loci for bipolar disorder on 18q21-22 and 8q24. Most recently, the families ascertained have been demonstrated to replicate the association of the G72/G30 gene complex on chromosome 13q33 with the bipolar disorder phenotype, and to uncover a novel association of BDNF with the illness. We now propose to ascertain and assess 112 additional nuclear families with a bipolar I proband and 2 or more siblings with a major affective disorder. We will analyze variations in clinical features in the ascertained families, including extending our hypothesis-driven analyses of bipolar II, psychotic bipolar disorder and panic disorder comorbidity. We will also pursue data-driven studies using factor analysis to derive and test potentially genetically meaningful phenotypic subtypes. Tests of familial aggregation of variables and factors will be performed, and positive results will be followed by covariate analyses of linkage results. A new genome-wide linkage scan will be performed by the Center for Inherited Disease Research (CIDR) in 2 parts: 105 (not previously scanned) families in year 1 and 112 families in year 5. The data will be analyzed both with standard linkage methods and with conditional logistic methods that allow for use of covariates such as clinical variables or factors, or other loci. The linkage data generated in year 1 will, among other things, provide a replication sample for the genotype-subphenotype studies referred to above. We will perform association studies through SNP genotyping (using the Illumina platform) in 4 chromosomal regions. 3 of these-13q31-33, 18q21-22 and 22q12-will be regions where our prior findings suggest both the likelihood of a bipolar disorder susceptibility gene and a potential genotype/subphenotype correlation. The 4th region will be a new 1, which we will only determine once we have analyzed the results from the new year 1 genome-wide linkage scan. Analyses of the SNP data will include covariates, when appropriate, and haplotype and partitioning of linkage approaches. Positive results will be followed up first with replication in an independent sample in our local labs. Replicated findings will be pursued through sequencing for mutation analysis and rare SNP discovery. These new variants would then be tested for association in our sample. The important findings that have already emerged from our very carefully assessed sample argue for the benefits of extending this valuable resource.

描述（由申请人提供）：该项目是约翰·霍普金斯大学，芝加哥大学和国家心理健康研究所的调查人员之间的一个3个站点合作的延续 - 这已经开发了一种双相情感障碍家庭资源，事实证明，该资源在验证临床基于临床的假设方面具有独特的价值。到目前为止，该项目从该项目提出的发现包括对双相情感型表型和精神病性躁郁症的分布和遗传显着性的首次系统研究。该项目还首先确定了18Q21-22和8Q24的躁郁症的重要候选基因座。最近，已证明这些家族已被证明是为了复制13q33染色体上的G72/G30基因复合物与双相情感障碍表型的关联，并发现BDNF与疾病的新型关联。现在，我们建议通过双极I概率和2个或更多患有主要情感障碍的兄弟姐妹确定和评估112个其他核心家庭。我们将分析确定家族的临床特征的变化，包括扩展了对假设驱动的双极II分析，精神病性躁郁症和恐慌症合并症。我们还将使用因子分析进行数据驱动的研究，以得出并测试潜在的遗传有意义的表型亚型。将进行变量和因子的家族性聚集测试，并将进行积极的结果，然后进行链接结果的协变量分析。遗传性疾病研究中心（CIDR）将在第1年的第1年和112个家庭中进行新的全基因组联系扫描（CIDR），以2部分：105（以前未经扫描）家庭进行。这些数据将通过标准的链接方法和有条件的逻辑方法进行分析，并允许使用诸如临床变量或因素或其他cliable或其他loci或其他clinical variables或其他loci或其他loci或其他网站。在第1年产生的链接数据将为上述基因型 - 表型研究提供复制样本。我们将通过4个染色体区域中的SNP基因分型（使用Illumina平台）进行关联研究。 This-13Q31-33、18Q21-22和22Q12的第3个中的3个将是我们先前的发现表明双相情感障碍敏感性基因的可能性和潜在的基因型/亚表格相关性。第四区将是一个新的1，只有一旦我们分析了新的1个基因组链接扫描的结果，我们才能确定。 SNP数据的分析将包括适当的协变量，以及链接方法的单倍型和分区。在我们本地实验室中的独立样本中，将首先随访积极的结果。复制的发现将通过测序进行突变分析和罕见的SNP发现来追求。然后，这些新变体将在我们的样本中进行关联测试。我们非常仔细评估的样本中已经出现的重要发现，争辩说扩展了这一宝贵资源的好处。