Genetic Linkage and Association in Bipolar Disorder

双相情感障碍的遗传连锁和关联

• 批准号: 7611971
• 负责人: James B. Potash
• 金额: $ 38.89万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7611971
• 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; 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; Reporting; Research; Research Personnel; Resources; SNP genotyping; Sampling; Scanning; Siblings; Signal Transduction; Site; Suicide attempt; Susceptibility Gene; Symptoms; System; Testing; 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 3-site collaboration 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 fourth region will be a new one, 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）：这个 3 个地点的合作开发了双相情感障碍家庭资源，该资源已被证明在测试有关疾病遗传异质性的临床假设方面具有独特的价值。迄今为止，该项目的研究结果包括首次对双相 II 表型和精神病性双相情感障碍的分布和遗传显着性进行系统研究。该项目还首次在 18q21-22 和 8q24 上鉴定出双相情感障碍的重要候选位点。最近，已确定的家族已被证明复制了染色体 13q33 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 与该疾病的新关联。我们现在建议确定和评估另外 112 个核心家庭，其中有 I 型双相情感障碍先证者和 2 个或更多兄弟姐妹患有严重情感障碍。我们将分析已确定家庭的临床特征差异，包括扩展我们对双相 II、精神病性双相情感障碍和恐慌症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，以推导和测试潜在的具有遗传意义的表型亚型。将进行变量和因素的家族聚集检验，阳性结果之后将进行连锁结果的协变量分析。遗传病研究中心 (CIDR) 将分两部分进行新的全基因组连锁扫描：第一年 105 个（之前未扫描）家族和第 5 年 112 个家族。数据将通过标准连锁进行分析方法和条件逻辑方法，允许使用协变量，例如临床变量或因素，或其他基因座。除其他外，第一年生成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（13q31-33、18q21-22 和 22q12）将是我们之前的研究结果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。第四个区域将是一个新区域，我们只有在分析了新的第一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）以及单体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。将通过突变分析和罕见 SNP 发现的测序来追求重复的结果。然后将在我们的样本中测试这些新变体的关联性。从我们经过仔细评估的样本中得出的重要发现证明了扩展这一宝贵资源的好处。

项目成果

Family-based association of FKBP5 in bipolar disorder.

FKBP5 在双相情感障碍中的基于家庭的关联。

• 发表时间: 2009-03
• 影响因子: 11
• 作者: Willour, V L;Chen, H;Toolan, J;Belmonte, P;Cutler, D J;Goes, F S;Zandi, P P;Lee, R S;MacKinnon, D F;Mondimore, F M;Schweizer, B;Bipolar Disorder Phenome Group;NIMH Genetics Initiative Bipolar Disorder Consortium;DePaulo Jr, J R;Gershon, E S
• 通讯作者: Gershon, E S

Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder.

精神分裂症和双相情感障碍的基因组扫描荟萃分析，第三部分：双相情感障碍。

• DOI: 10.1086/376547
• 发表时间: 2003-07-01
• 期刊: American journal of human genetics
• 影响因子: 9.8
• 作者: R. Segurado;S. Detera;D. Levinson;C. Lewis;M. Gill;J. Nurnberger;N. Craddock;J. DePaulo
• 通讯作者: J. DePaulo

The bipolar disorder phenome database: a resource for genetic studies.

双相情感障碍表型数据库：遗传研究资源。

• 发表时间: 2007-08
• 作者: Potash, James B;Toolan, Jennifer;Steele, Jo;Miller, Erin B;Pearl, Justin;Zandi, Peter P;Schulze, Thomas G;Kassem, Layla;Simpson, Sylvia G;Lopez, Victor;NIMH Genetics Initiative Bipolar Disorder Consortium;MacKinnon, Dean F;McMahon, Francis J
• 通讯作者: McMahon, Francis J

Common and rare variants of DAOA in bipolar disorder.

双相情感障碍中 DAOA 的常见和罕见变异。

• 发表时间: 2009-10-05
• 作者: Maheshwari, Manjula;Shi, Jiajun;Badner, Judith A;Skol, Andrew;Willour, Virginia L;Muzny, Donna M;Wheeler, David A;Gerald, Fowler R;Detera;McMahon, Francis J;Potash, James B;Gershon, Elliot S;Liu, Chunyu;Gibbs, Richard A
• 通讯作者: Gibbs, Richard A

Genome-wide scan of bipolar II disorder.

II型双相情感障碍的全基因组扫描。

• 发表时间: 2007-09
• 影响因子: 5.4
• 作者: Nwulia, Evaristus A;Miao, Kuangyi;Zandi, Peter P;Mackinnon, Dean F;DePaulo Jr, J Raymond;McInnis, Melvin G
• 通讯作者: McInnis, Melvin G