Genetic Determinants of Bipolar Disorder

描述（由申请人提供）： 这个修订的合作R 01应用程序的目的是确定易感基因的双相情感障碍（BD）通过测试单核苷酸多态性（SNP）的染色体区域先前与BD。我们的建议是双相情感障碍系统治疗增强计划（STEP-BD）的辅助研究，这是一项涉及约5000名受影响个体的大型治疗研究。样本将包括来自STEP-BD的同意先证者（n = 1780）、同意的家庭成员和无关对照样本。由于其前所未有的规模和纵向性质，STEP-BD为BD的遗传解剖提供了一个独特的机会。我们会分以下阶段进行研究：1）对BD的可用基因组扫描进行荟萃分析，以鉴定最可能具有易感性基因座的区域，2）使用合并的基因分型方法在550个病例和550个无关对照的筛选样品中测试这些连锁峰下的SNP，3）使用基于家族的单倍型分析和更集中和密集的SNP图谱，在1361个核心家族的基于家族的样本中进行随访正关联，和4）进行二次分析以评估相关基因座之间的表位并检查表型亚型。该建议结合了STEP-BD队列提供的系统表型和统计能力的优势，以及创新的分子和统计遗传学方法，以允许严格评估先前连锁研究最强烈暗示的染色体区域。自上次提交以来，该提案的可行性得到了进一步提高，因为NIMH将单独资助从STEP-BD病例中收集DNA和表型数据，以建立科学界的储存库。此外，Nimgaonkar博士和Smoller博士（当前提案的PI）将代表STEP-BD研究共同指导这项工作。 鉴定易感基因将代表理解BD病理生理学的重大进展，并可能指导更有效和更有针对性的治疗方法的开发。这项大型研究的一个重要成果是扩大了储存库，包括亲属和独立对照样本的DNA数据，从而促进了未来的遗传研究。

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.