Genetic Linkage Studies in Bipolar Disorder Families

描述（由申请人提供）：该项目是约翰霍普金斯大学、芝加哥大学和国家精神卫生研究所三方合作的延续，该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该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，该项目的发现包括对双相情感障碍II型和精神病性双相情感障碍的分布和遗传显著性的首次系统研究。该项目还首次确定了18q21-22和8q24上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112个有双相I先证者和2个或更多兄弟姐妹有严重情感障碍的核心家庭。我们将分析在确定的家庭中临床特征的变化，包括扩展我们对双相情感障碍II、精神病性双相情感障碍和惊恐障碍共病的假设驱动分析。我们还将进行数据驱动的研究，使用因子分析来推导和测试潜在的遗传上有意义的表型亚型。将进行变量和因素的家族性聚集检验，阳性结果将随后进行关联结果的协变量分析。新的全基因组连锁扫描将由遗传疾病研究中心（CIDR）分两部分进行：第1年的105个（以前未扫描的）家庭和第5年的112个家庭。数据将用标准链接方法和允许使用协变量（如临床变量或因素或其他基因座）的条件逻辑方法进行分析。除其他事项外，第一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。其中的3个-13q31-33, 18q21-22和22q12将是我们先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/亚表型相关的区域。第四个区域将是一个新的1，我们只有在分析了新的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，单倍型和连锁划分方法。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相关性。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展这一宝贵资源的好处。

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.