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: 6612911
• 负责人: Elliot S Gershon
• 金额: $ 61.18万
• 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/6612911
• 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，钙蛋白酶-10和NOD 2作为糖尿病和炎症性肠病的易感基因的成功鉴定为常见疾病遗传学树立了强有力的先例，有利于疾病基因检测的策略，其中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）是一种具有复杂遗传模式的常见疾病（终生人群患病率1%）。 对BP家族的多重连锁研究已经报道，在人类基因组的几个区域间歇性地获得阳性结果。 对所有已发表的BP全基因组扫描的荟萃分析是检测最有希望的定位克隆区域的合理方法;我们的荟萃分析仅在两个区域13 q32和22 q11中发现了显着的连锁。 染色体13 q32是一个区域，显示连锁BP和精神分裂症，该地区的特点是需要在这两种疾病的定位克隆研究。从人类基因组计划和塞雷拉地图开始，我们最近开发了13 q32区域的完整物理地图，填补了已发表地图中的所有空白。我们在这里提出了一个完整的13 q32区域的分子特征，作为一个框架，用于识别的易感性变异BP。 我们正在创建一个13 q32-q33的高密度SNP图谱，并由我们正在开发的软件支持。 为了丰富我们的SNP数据库中不常见的SNP和功能上有趣的变异与BP疾病的易感性的潜力，7个BP个人从家庭与13 q32的正连锁评分，和3个对照个人，将有突变分析的每个基因和EST在该地区已知的。 将以1/20 kb的平均密度，对来自196例单例或受影响同胞对的BP患者的DNA进行与父母对照的关联研究，这些患者具有2个基因分型的父母，以及其他无关的BP。 这些样本取自13 q上具有暗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、单倍型共享的衰减以及其他分析。 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体型分析以证实结果，以及与疾病相关的临床内表型的检测。