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.

去年成功鉴定出 calpain-10 和 NOD2 作为糖尿病和炎症性肠病的易感基因，为常见疾病遗传学奠定了强有力的先例，有利于疾病基因检测策略，其中检测连锁并随后进行连锁不平衡研究该地区。 双相情感障碍 (BP) 是一种具有复杂遗传模式的常见疾病（人群终生患病率为 1%）。 已经报道了针对 BP 家族的多项连锁研究，在人类基因组的几个区域中取得了间歇性的阳性结果。 对所有已发表的 BP 全基因组扫描进行荟萃分析是检测最有希望进行定位克隆的区域的合理方法；我们的荟萃分析发现仅在两个区域（13q32 和 22q11）存在显着关联。 染色体 13q32 是一个与 BP 和精神分裂症相关的区域；这两种疾病的定位克隆研究都需要对该区域进行表征。从人类基因组计划和 Celera 图谱开始，我们最近开发了 13q32 区域的完整物理图谱，弥补了已发布图谱中的所有现有空白。我们在此提出 13q32 区域的完整分子表征，作为识别 BP 易感性变异的框架。 我们正在创建特定于 13q32-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，以获取可能对 BP 疾病易感的罕见 SNP 和功能上有趣的变异，来自 13q32 上具有正连锁评分的家庭的 7 名 BP 个体和 3 名对照个体，将对已知的每个基因和 EST 进行突变分析。地区。 将以 1/20 kb 的平均密度，对来自 196 名单身或受影响的 BP 患者（有 2 个基因型父母）的 DNA 以及其他不相关的 BP 进行与父母对照的关联研究。 这些样本取自 13q 上具有暗示性或轻微正向连锁统计的连锁序列。 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。 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分析以证实结果，以及测试与疾病相关的临床内表型。