Core--Linkage

核心--联动

• 批准号: 6645009
• 负责人: MATTHEW J FARRER
• 金额: $ 29.31万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6645009
• 关键词: Parkinson's disease; biomedical facility; family genetics; gene mutation; genetic markers; genotype; human genetic material tag; linkage disequilibriums; linkage mapping; neurogenetics; statistics /biometry

The major role of the Linkage Core will be to genetically assign families, largely, though not exclusively, derived from the Clinical Core, into the appropriate classes. It will be our intention to separate families by genetic analysis into four groups: (1) those with mutations in known genes (synuclein, parkin, tau for example); (2) those which probably have a pathogenic locus on 4p (parsed to Project 1); (3) those which have a pathogenic locus on chromosome 2p (parsed to Project 2) and (4) those which probably have an underlying genetic etiology, elsewhere in the genome. Families with mutation (s) in known genes will be identified by searching for segregation of marker genotypes in affecteds individuals (by both non-parametic haplotype and model-based linkage analysis) in regions formerly liked to parkinsonism/parkinson's disease. Sequencing known genes in probands will identify mutations. Families may be parsed into chromosome 2p and 4p as appropriate by comparison of autosomal dominant affected-only linkage simulation and observed lod scores/haplotype analysis. Further analysis of genetic heterogeneity among putative 2p and 4p linked families, haplotype analysis of cross-over data to prioritize regions for physical mapping (Projects 1&2) and ultimately linkage disequilibrium analysis within minimal "obligate" regions will be performed. Families excluded by linkage and lack of haplotype sharing among affecteds will be pooled into groups based on their apparent mode of inheritance (AD, AR X-linked, oligogenic/multifactorial), their phenotype (age of onset, clinical presentation, pathology, ethic and geographical origin) for future genetic studies. As new genomic loci/genes for parkinsonism become identified these will be tested by the mechanisms we have outlined. Concomitantly, the Clinical Core will expand the largest families (or ones that have the greatest potential information content for linkage/easiest to ascertain) both genealogically and in terms of sample collection. Power analysis by the Linkage Core will help prioritize family collection. Periodically, when families have been collected that are of sufficient size and statistical likelihood to successfully identify a new locus for Parkinson's disease, a genome search will be performed.

联动核心的主要作用是通过基因将家族（大部分但不完全源自临床核心）分配到适当的类别。 我们的目的是通过遗传分析将家庭分为四组：(1) 已知基因发生突变的家庭（例如突触核蛋白、parkin、tau）； （2）可能在4p上有致病位点的（解析至项目1）； (3) 那些在 2p 染色体上有致病位点的基因（解析为项目 2）和 (4) 那些可能在基因组其他地方具有潜在遗传病因的基因。将通过在以前喜欢帕金森病/帕金森氏病的区域中搜索受影响个体中标记基因型的分离（通过非参数单倍型和基于模型的连锁分析）来鉴定已知基因中具有突变的家族。 对先证者中的已知基因进行测序将识别突变。 通过比较常染色体显性仅受影响的连锁模拟和观察到的 lod 分数/单倍型分析，可以将家族酌情解析为染色体 2p 和 4p。 将进一步分析假定的 2p 和 4p 连锁家族之间的遗传异质性、交叉数据的单倍型分析以优先考虑物理作图区域（项目 1 和 2），并最终在最小“必然”区域内进行连锁不平衡分析。 由于连锁和受影响者之间缺乏单倍型共享而被排除的家庭将根据其明显的遗传模式（AD、AR X连锁、寡基因/多因素）、其表型（发病年龄、临床表现、病理学、伦理和地理起源）用于未来的遗传学研究。 随着帕金森病的新基因组位点/基因被识别，这些将通过我们概述的机制进行测试。 与此同时，临床核心将在谱系和样本收集方面扩大最大的家族（或具有最大潜在联系信息内容/最容易确定的家族）。 Linkage Core 的功率分析将有助于优先考虑家庭收集。 当收集到的家族具有足够的规模和统计可能性以成功识别帕金森病的新基因座时，将定期进行基因组搜索。