A Collaborative Genomic Study of Bipolar Disorder

描述（由申请人提供）：自1988年以来，NIMH遗传学倡议一直支持双相情感障碍（BP）研究的国家资源。到1997年，对153个多重家族进行了评估，提供了细胞系、DNA和匿名临床数据。现在这是一个公开的资源，分析结果已经发表。1998年开始的第二次工作是确定500对新的BP同胞对，并已超过这一目标，另外确定、访问了523对BP同胞对，并收集了DNA样本。遗传疾病研究中心（CIDR）已完成对237对兄弟姐妹家庭的全基因组扫描，其余309个家庭将在2003年由CIDR进行基因分型。该资源是同类资源中最大的，已经揭示了染色体6q和17q上连锁区域的证据。它还证实了染色体22q上的一个位点，并支持了1p、10p、16p、13q和21q上的区域。积累的连锁数据暗示了其他染色体区域。我们建议扩展国家遗传资源，包括5000个不相关的BP先证者和2000个父母样本，用于病例对照和基于家庭的关联研究。对照样本将通过NIMH遗传学倡议国家资源获得。将在11个地点（先前参与的10个地点加上将提供非裔美国人先证者的霍华德大学）确定和评估先证者和父母。该样本将成为连锁区域内精细尺度连锁不平衡定位以及候选基因关联研究的国家资源。子样本中的亲本dna将允许控制种族分层。生物信息学技术将发展并支持候选区域的基因组分析，以帮助选择snp和其他多态性标记（包括候选基因周围和内部），以及引物设计。基因分型将在8个实验室间协调，采用知情的分步方法，首先对目前699个家系进行标准微卫星定位，然后在一个工业实验室进行单核苷酸多态性的合同基因分型，然后在个别地点的实验室继续进行后续的基因分型和候选基因和区域测序。更大的病例对照样本的SNP分型将在合作研究的最后一年进行。对现有的兄弟姐妹家庭进行分析，加上这一大批病例和对照，应该可以确认在这一资助期间的几个易感基因。

DESCRIPTION (provided by applicant): Since 1988 the NIMH Genetics Initiative has supported a national resource for the study of bipolar disorder (BP). By 1997 153 multiplex families were assessed, providing cell lines, DNA, and anonymized clinical data. This is now a publicly available resource and analytic results have been published. A second effort commenced in 1998 to ascertain 500 new BP sib pairs and this goal has been exceeded with 523 additional BPI sib pairs ascertained, interviewed, and a DNA sample collected. A genome wide scan has been completed at the Center for Inherited Disease Research (CIDR) on 237 sib pair families and the remaining 309 families will be genotyped by CIDR during 2003. This resource, the largest of its kind, has revealed evidence for areas of linkage on chromosomes 6q and 17q. It has also provided confirmation of a locus on chromosome 22q and support for areas on 1p, 10p, 16p, 13q, and 21q. Accumulating linkage data has implicated other chromosomal regions. We propose an extension of the national genetic resource to include a sample of 5000 unrelated BP probands and 2000 parents for case-control, and family-based association studies. Control samples will be obtained through the NIMH Genetics Initiative national resource. Probands and parents will be ascertained and assessed at eleven sites (the ten sites previously participating plus Howard University, which will provide African-American probands). This sample will be a national resource for fine scale linkage disequilibrium mapping within regions of linkage, as well as candidate gene association studies. Parental DNAs in a subsample will allow control for ethnic stratification. Bioinformatics techniques will be developed and supported for genomic analysis of candidate regions, to assist selection of SNPs and other polymorphic markers (including surrounding and within candidate genes), and primer design. The genotyping will be coordinated across 8 labs with an informed step-wise approach, beginning with standard microsatellite mapping of the current set of 699 pedigrees, followed by contract genotyping of SNPs in an industrial laboratory, and continuing with follow-up genotyping and sequencing of candidate genes and regions in laboratories at the individual sites. SNP typing of the larger case-control sample will occur in the final year of the collaborative study. Analysis of the existing sib pair families plus this large set of cases and controls should permit the confirmation of several vulnerability genes during this grant period.