Core--Linkage

Linkage核心的主要作用将是从基因上将主要来自临床核心的家庭分配到适当的类别中，尽管不是唯一的。我们打算通过基因分析将家系分为四组：(1)那些已知基因突变的家庭(例如，突触核蛋白、parkin、tau)；(2)那些可能在4p上有致病基因的家庭(解析到项目1)；(3)那些在染色体2p上有致病基因的家庭(解析到项目2)；以及(4)那些可能有潜在遗传病因的家庭，在基因组的其他地方。已知基因突变的家系(S)将通过寻找帕金森病/帕金森病易患地区受影响个体的标记基因分离(通过非顺应性单倍型和基于模型的连锁分析)来识别。对先证者的已知基因进行测序将识别突变。通过比较常染色体显性遗传连锁模拟和观察到的Lod评分/单倍型分析，可将家系适当地解析为2p和4p染色体。将进一步分析假定的2p和4p连锁家系之间的遗传异质性，对交叉数据进行单倍型分析，以确定物理作图区域的优先顺序(项目1和2)，并最终在最小的“专有”区域内进行连锁不平衡分析。被排除在外的家系将根据其明显的遗传模式(AD、AR X连锁、少基因/多因素)、其表型(发病年龄、临床表现、病理、伦理和地理起源)被合并为组，用于未来的遗传学研究。随着帕金森病新的基因组位点/基因的确定，这些基因将通过我们概述的机制进行测试。与此同时，临床核心将在家谱和样本收集方面扩大最大的家族(或具有最大潜在联系/最容易确定的信息内容的家族)。Linkage Core的功率分析将有助于确定家庭收集的优先顺序。定期地，当收集到具有足够大小和统计可能性的家系，成功地识别出帕金森氏病的新基因座时，将进行基因组搜索。

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.