Genetic Determinants of Bipolar Disorder

描述(由申请人提供)： 这个经过修订的协作R01应用程序旨在通过测试以前与双相情感障碍(BD)相关的染色体区域的单核苷酸多态(SNPs)来识别双相情感障碍(BD)的易感基因。我们的建议是双相情感障碍系统治疗强化计划(STEP-BD)的一项辅助研究，这是一项涉及大约5000名受影响个人的大型治疗研究。样本将由同意的STEP-BD先证者(n=1780)、同意的家庭成员和一个不相关的对照样本组成。由于其前所未有的大小和纵向性质，STEP-BD为BD的基因解剖提供了独特的机会。我们将分以下阶段进行这项研究：1)对现有的BD基因组扫描进行荟萃分析，以确定最有可能包含易感基因座的区域；2)使用汇集的基因分型方法，在550例病例和550名无关对照的筛查样本中，测试这些连锁峰下的SNPs；3)使用基于家族的单倍型分析，使用更集中和更密集的SNP图谱，对1361个核心家庭的家系样本进行后续的正相关性分析；以及4)进行二次分析，以评估相关基因座之间的外露，并检查表型亚型。这一建议将STEP-BD队列提供的系统表型和统计能力的优势与创新的分子和统计遗传学方法结合在一起，以允许对先前连锁研究中最强烈涉及的染色体区域进行严格评估。自上次提交以来，这项建议的可行性得到了进一步提高，因为NIMH将单独为收集STEP-BD病例的DNA和表型数据提供资金，以建立科学界的储存库。此外，Nimgaonkar博士和Smoller博士(当前提案的个人资料)将代表STEP-BD研究共同指导这项工作。 易感基因的识别将代表着对BD病理生理学理解的重大进步，并可能指导更有效和更有针对性的治疗方法的发展。这项大型研究的一个重要好处是扩大了资料库，包括亲属和对照的独立样本的DNA数据，从而促进了未来的基因研究。

DESCRIPTION (provided by applicant): This revised collaborative R01 application is designed to identify susceptibility genes for bipolar disorder (BD) by testing single nucleotide polymorphisms (SNPs) across chromosomal regions previously linked to BD. Our proposal is an ancillary study to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a large treatment study involving approximately 5000 affected individuals. The sample will consist of consenting probands from STEP-BD (n = 1780), consenting family members, and a sample of unrelated controls. Because of its unprecedented size and longitudinal nature, STEP-BD provides a unique opportunity for the genetic dissection of BD. We will conduct the study in stages as follows: 1) perform a meta-analysis of available genome scans of BD to identify regions most likely to harbor susceptibility loci, 2) use pooled genotyping methods to test SNPs under these linkage peaks in a Screening Sample of 550 cases and 550 unrelated controls, 3) follow-up positive associations in a Family-Based Sample of 1361 nuclear families using family-based and haplotype analyses with a more focused and dense SNP map, and 4) perform secondary analyses to evaluate epitasis among associated loci and examine phenotypic subtypes. This proposal combines the advantages of systematic phenotyping and statistical power offered by the STEP-BD cohort together with innovative molecular and statistical genetic methods to permit rigorous evaluation of chromosomal regions most strongly implicated by prior linkage studies. The feasibility of this proposal has been further enhanced since the previous submission because NIMH will be separately funding the collection of DNA and phenotypic data from STEP-BD cases to establish a repository for the scientific community. Moreover, Dr. Nimgaonkar and Dr. Smoller (PIs for the current proposal) will be co-directing this effort on behalf of the STEP-BD study. Identification of liability genes would represent a major advance in understanding the pathophysiology of BD, and might guide the development of more effective and targeted treatments. An important dividend of this large study will be the expansion of the repository to include DNA data on relatives and on an independent sample of controls, thus facilitating future genetic studies.