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.

过去一年中，Calpain-10和Nod2成功鉴定为糖尿病和炎症性肠病中的易感基因，为常见疾病遗传学树立了强大的先例，有利于检测并在该地区内部检测并进行连接的疾病基因检测策略。 双相情感障碍（BP）是一种具有复杂遗传模式的常见疾病（终生人口流行1％）。 已经报道了有关BP家族的多个连锁研究，在人类基因组的几个区域中，间歇性的阳性结果。 对BP的所有已发表的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。我们的荟萃分析发现仅在两个区域（13q32和22q11）中有显着的联系。 13q32染色体是一个与BP和精神分裂症联系在一起的区域。两种疾病中的位置克隆研究都需要该区域的表征。从人类基因组项目和CELERA地图开始，我们最近开发了13q32区域的完整物理图，缩小了已发表的地图中的所有现有差距。我们在这里提出了13q32区域的完整分子表征，作为识别BP易感变体的框架。 我们正在创建一个针对13q32-Q33的高密度SNP映射，并在我们正在开发的软件中支持。 为了丰富我们的SNP数据库，用于罕见的SNP和功能有趣的变体，具有易感性BP疾病的可能性，来自13q32链接分数的家庭的7个BP个体以及3个对照个体将对该地区的每个基因和EST进行突变分析。 与父母对照组的关联研究将以1/20 Kb的平均密度进行，或对196个单胎的DNA或患有2个基因分型父母的BP患者和其他无关BP的BP患者进行研究。 这些样本取自具有13q上具有暗示性或略有正面链接统计的链接系列。 统计分析将包括单个基因座和单倍型分析，链接证据的分区，单倍型共享的衰减以及其他分析。 进一步分析阳性不平衡结果将包括其他基因分型和单倍型，以证实结果，并测试与疾病相关的临床内表型。