Genetic Linkage Studies in Bipolar Disorder Families

双相情感障碍家庭的遗传连锁研究

• 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
• 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

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）：该项目是一个3-site合作的延续-在约翰霍普金斯，芝加哥大学和国家精神卫生研究所的研究人员之间-已经开发了一个双相情感障碍家庭资源，已被证明是独特的价值在测试临床为基础的假设有关的疾病的遗传异质性。到目前为止，该项目的发现包括双相II型和精神病性双相障碍的分布和遗传显著性的首次系统研究。该项目还首次在18 q21 -22和8 q24上确定了双相情感障碍的重要候选位点。最近，已证实的家庭复制染色体13 q33上的G72/G30基因复合体与双相情感障碍表型的关联，并揭示了BDNF与疾病的新关联。我们现在建议确定和评估112个额外的核心家庭，一个双相I型先证者和2个或更多的兄弟姐妹与一个重大的情感障碍。我们将分析已确定的家族中临床特征的变化，包括扩展我们对双相II型、精神病性双相障碍和惊恐障碍合并症的假设驱动分析。我们还将利用因子分析进行数据驱动的研究，以获得和测试潜在的遗传意义的表型亚型。将进行变量和因素的家族聚集性检验，阳性结果后将进行连锁结果的协变量分析。遗传疾病研究中心（CIDR）将分两部分进行新的全基因组连锁扫描：第1年105个（以前未扫描）家庭和第5年112个家庭。将使用标准连锁方法和允许使用协变量（如临床变量或因子或其他基因座）的条件logistic方法分析数据。除其他外，第1年产生的连锁数据将为上述基因型-亚表型研究提供复制样本。我们将通过SNP基因分型（使用Illumina平台）在4个染色体区域进行关联研究。其中3个区域-13 q31 -33，18 q21 -22和22 q12-将是我们先前的发现表明双相情感障碍易感基因的可能性和潜在的基因型/亚表型相关性的区域。第四个区域将是新的1，我们将只在分析新的1年全基因组连锁扫描的结果后才能确定。SNP数据的分析将包括协变量，适当时，和单倍型和连锁方法的划分。阳性结果将首先在我们当地实验室的独立样本中进行复制。重复的发现将通过测序进行突变分析和罕见的SNP发现。然后在我们的样本中测试这些新变体的关联性。从我们非常仔细评估的样本中已经出现的重要发现证明了扩大这一宝贵资源的好处。