Genetic Analysis Of Alzheimer s Disease

与翻译基因组学合作，完成了阿尔茨海默氏病全基因组关联分析，这项工作涉及超过1/2亿个基因类型的产生和分析；这些分析现已发布到公共领域。这项工作清楚地表明，载脂蛋白E基因座是阿尔茨海默病的单一共同遗传危险因素。随后的分析揭示了GAB2-A基因变异作为阿尔茨海默病新的危险因素的潜在作用。除了这项工作外，我们已经开始收集由全基因组SNP协会进行基因分型的受试者和神经学正常对照的相关表型(例如痴呆症)，这些受试者也在实验室内进行基因分型，以增加初始研究的力量。 参与全基因组关联研究的样本子集是由神经遗传学实验室从脑库收集的；这些阿尔茨海默病样本的表达数据是去年进行的，目前正在分析这些数据，并与对照样本中的类似数据进行比较，试图生成阿尔茨海默病大脑的表达定量特征基因座图，并潜在地确定神经学正常受试者和阿尔茨海默病患者大脑之间表达差异的遗传基础。 对新疾病人群中APP和早老素基因的重新测序分析使人们对先前报道的早老素-1和早老素-2突变的潜在致病性有了新的见解。此外，我们正在分析没有已知突变的年轻发病样本和使用密集SNP基因分型怀疑父母血缘关系的家庭，试图确定阿尔茨海默病的新的隐性基因座，这项工作的第一部分已于今年发表，第二阶段涉及更大的年轻发病但异种繁殖的人口，正在进行中。

In collaboration with translational genomics a genome wide association analysis in Alzheimers disease was completed, this work involved generation and analysis of more than 1/2 billion genotypes; and these analyses have now been released into the public domain. This work showed elegantly that the APO E locus is the single over-riding common genetic risk factor for Alzheimers disease. Subsequent analysis revealed a potential role for genetic variability in GAB2-A as a novel risk factor in Alzheimers disease. In addition to this work we have begun collecting related phenotypes (for eg dementia) from subjects genotyped by genome wide SNP association and from neurologically normal controls also genotyped within the laboratory in order to increase the power of the initial study. A subset of the samples involved in the genome wide association study were collected by the laboratory of neurogenetics from brain banks; generation of expression data in these Alzheimer's disease samples was performed last year and these data are currently being analyzed and compared to similar data in control samples in an attempt to produce an expression quantitative trait locus map of the Alzheimer's disease brain and to potentially identify a genetic basis of expression differences observed between brains from neurologically normal subjects and those with Alzheimer's disease. Resequencing analysis of APP and presenilin genes in novel disease populations has lead to new insights into the potential pathogenicity previously reported presenilin-1 and presenilin-2 mutations. In addition we are analyzing young-onset samples without known mutations and families where parental consanguinity is suspected using dense SNP genotyping in an attempt to identify novel recessive loci for Alzheimer's disease, the first portion of this work was published this year and a second phase, involving a larger young-onset but outbred population, is ongoing.