Fine Genomic Mapping of 13q32 in Bipolar Disorder

双相情感障碍 13q32 的精细基因组定位

• 批准号: 6463293
• 负责人: Elliot S Gershon
• 金额: $ 55.86万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-08 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6463293
• 关键词: biotechnology; bipolar depression; chromosome aberrations; clinical research; computer program /software; data collection methodology /evaluation; family genetics; genetic susceptibility; genotype; human genetic material tag; linkage disequilibriums; linkage mapping; meta analysis; polymerase chain reaction; restriction fragment length polymorphism; single nucleotide polymorphism; statistics /biometry

The successful identification of calpain-10 and NOD2 as susceptibility genes in diabetes and inflammatory bowel disease in the past year have set powerful precedents for common disease genetics, favoring a strategy for disease gene detection where linkage is detected and followed up by linkage disequilibrium studies within the region. Bipolar disorder (BP) is a common disease (lifetime population prevalence 1 percent) with a complex inheritance pattern. Multiple linkage studies on families with BP have been reported, with intermittently positive results in several regions of the human genome. Meta-analysis of all published whole-genome scans of BP is a rational method for detecting the most promising regions for positional cloning; our meta-analysis found significant linkage in only two regions, 13q32 and 22q11. Chromosome 13q32 is a region that shows linkage to both BP and Schizophrenia; characterization of the region is needed for positional cloning studies in both disorders. Starting with the Human Genome Project and Celera maps, we have recently developed a complete physical map of the 13q32 region, closing all existing gaps in the published maps. We propose here a complete molecular characterization of the 13q32 region, as a framework for identification of a susceptibility variant for BP. We are creating a high density SNP map specific for 13q32-q33, supported by software we are developing. To enrich our SNP database for uncommon SNPs and functionally interesting variants with a potential for susceptibility to BP illness, 7 BP individuals from families with positive linkage scores on 13q32, and 3 control individuals, will have mutational analysis of every gene and EST known in the region. Association studies with parental controls will be done, at an average density of 1/20 kb, on DNA from 196 singletons or affected-sib-pairs of BP patients with 2 genotyped parents, and additional unrelated BPs. These samples are taken from linkage series with suggestive or slightly positive linkage statistics on 13q. Statistical analyses will include single locus and haplotype analyses, partition of linkage evidence, decay of haplotype sharing, and other analyses. Further analysis of positive disequilibrium results will include additional genotyping and haplotyping to corroborate the result, and testing for clinical endophenotypes associated with disease.

在过去的一年中，Calain-10和NOD2成功地被确定为糖尿病和炎症性肠病的易感基因，为常见疾病遗传学开创了强有力的先例，支持了一种疾病基因检测的策略，即检测到连锁并在该区域内进行连锁不平衡研究。双相情感障碍(BP)是一种常见疾病(终生人口患病率为1%)，具有复杂的遗传模式。关于BP家族的多个连锁研究已有报道，在人类基因组的几个区域断断续续地取得了积极的结果。对所有已发表的BP全基因组扫描的荟萃分析是检测位置克隆最有希望的区域的合理方法；我们的荟萃分析只在13q32和22q11这两个区域发现了显著的连锁。染色体13q32是一个与BP和精神分裂症都有关联的区域；在这两种疾病中进行位置克隆研究都需要对该区域进行特征描述。从人类基因组计划和Celera图谱开始，我们最近绘制了一张完整的13q32区域物理图谱，填补了现有图谱中的所有空白。我们在此提出了13q32区域的完整分子特征，作为鉴定BP易感变异的框架。在我们正在开发的软件的支持下，我们正在创建专门针对13q32-q33的高密度SNP图谱。为了丰富我们的SNP数据库，寻找可能对BP疾病易感的罕见SNP和功能有趣的变异，来自13q32上连锁得分为正的7个BP个体和3个对照个体，将对该地区已知的每个基因和EST进行突变分析。与父母对照的关联研究将在平均密度为1/20kb的情况下，对196名具有2个基因型的BP患者的独生子女或受影响的同胞对的DNA进行研究，以及其他不相关的BP。这些样本取自13q上具有提示性或轻微正连锁统计的连锁系列。统计分析将包括单基因座和单倍型分析，连锁证据的划分，单倍型共享的衰退，以及其他分析。对阳性不平衡结果的进一步分析将包括额外的基因分型和单倍型以证实结果，以及与疾病相关的临床内表型测试。