Next Generation Mendelian Genetics in Familial Alzheimer Disease

家族性阿尔茨海默病的下一代孟德尔遗传学

• 批准号: 8462192
• 负责人: Zoran Brkanac
• 金额: $ 55.52万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462192
• 关键词: Abbreviations; Accounting; Affect; Age; Aging; Alzheimer' s Disease; Architecture; Bioinformatics; Candidate Disease Gene; Case-Control Studies; Code; Collection; Data; Databases; Deposition; Detection; Development; Diagnostic; Diagnostic tests; Disease; Disease Progression; Etiology; Evaluation; Family; Family member; Foundations; Gene Mutation; Generations; Genes; Genetic; Genetic Heterogeneity; Genome; Genomics; Genotype; Goals; Individual; Institutes; Late Onset Alzheimer Disease; Maps; Methods; Minority; Molecular; Molecular Diagnosis; Morbidity - disease rate; Mutation; National Institute of Mental Health; Onset of illness; Outcome; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Population Control; Presenile Alzheimer Dementia; Prevention; Proteins; Research; Research Personnel; Resources; Risk; Sampling; Science; Sequence Analysis; Technology; Therapeutic; Universities; Validation; Variant; Washington; Work; base; case control; data sharing; disorder prevention; exome; exome sequencing; familial Alzheimer disease; genetic pedigree; genome wide association study; improved; in vitro Model; innovation; mortality; next generation; next generation sequencing; novel; presenilin-1; presenilin-2; proband; public health relevance; segregation; therapeutic target; transmission process

DESCRIPTION (provided by applicant): Although it is well established that familial Alzheimer disease (AD) has a strong genetic basis, additional Mendelian genes remain to be identified. Mutations in the APP, PSEN1 or PSEN2 genes are involved in minority of AD families and are characterized with early disease onset. Large genome-wide association studies have not found strong evidence for the contribution of common variants besides the APOE gene. Although many families with pedigrees suggestive of autosomal dominant inheritance have been described and linkage studies have found evidence for multiple contributing loci, no new genes have been identified in the last 20 years. The goal of this proposal is to apply novel analytic approaches to identify families in which AD is likely to have a single gene etiology and to utilize next generation sequencing technologies to find these genes. The University of Washington (UW) AD collection contains more than twenty families where pedigrees are consistent with Mendelian inheritance. To identify additional families where single genes are likely to be causal, we will use the existing, well characterized National Institute of Aging (NIA) and National Institute of Mental Health (NIMH) AD collections with more than 700 families. In these collections, for which extensive genotype data is available, we will perform segmental Identity-by-Descent (IBD) mapping and Homozygosity-by-Descent (HBD) analysis to detect families that share a common ancestor within the past three to nine generations. Given the ascertainment of probands based on disease status it is expected that the relatedness uncovered by these analyses reflects inheritance of a shared causal mutation from the recent common ancestor. To identify candidate genes in UW families with pedigrees, and NIA and NIMH families that share recent ancestry as defined by IBD and HBD analyses, we will perform exome capture and massively parallel sequencing followed by bioinformatics analysis and evaluation of co-segregation. To establish association of identified candidate genes with AD we will perform gene-based mutational load case-control studies with more than 200 familial AD cases and 2,000 population controls. Finally, to facilitate validation of our findings we will deposit sequence information in a public database. The identification of novel AD genes would be a significant step towards an increased understanding of the genetic architecture of AD. These genes would enable development of diagnostic tests and implicate new or expanded molecular pathways involved in AD pathogenesis. Examination of these pathways will likely reveal additional therapeutic targets. This study will also establish the utility of our innovative analytical approach combined with exome sequencing as a powerful method for the identification of genes for Mendelian forms of common genetically heterogeneous disorders.

描述(由申请人提供)：尽管家族性阿尔茨海默病(AD)有很强的遗传基础已被公认，但其他孟德尔基因仍有待识别。APP、PSEN1或PSEN2基因突变与少数AD家系有关，具有发病早的特点。大型全基因组关联研究没有发现除APOE基因以外的常见变异的贡献的有力证据。虽然已经描述了许多具有常染色体显性遗传的家系，连锁研究也发现了多个致病基因座的证据，但在过去的20年里没有发现新的基因。这项建议的目标是应用新的分析方法来识别AD可能具有单基因病因的家系，并利用下一代测序技术来寻找这些基因。华盛顿大学(UW)的AD收藏包含了20多个谱系与孟德尔遗传一致的家庭。为了确定更多的单基因可能是因果关系的家庭，我们将使用现有的、具有良好特征的国家老龄研究所(NIA)和国家精神卫生研究所(NIMH)AD收集，包括700多个家庭。在这些拥有大量基因数据的集合中，我们将进行逐个世代的分段同一性(IBD)作图和逐个世代的纯合性(HBD)分析，以检测在过去三到九代中拥有共同祖先的家庭。考虑到根据疾病状况确定先证者，预计这些分析发现的相关性反映了来自最近共同祖先的共同原因突变的遗传。为了确定UW家系中的候选基因，以及IBD和HBD分析中具有相同近亲的NIA和NIMH家族，我们将进行外显子捕获和大规模平行测序，然后进行生物信息学分析和共分离评估。为了建立已识别的候选基因与AD的关联，我们将对200多个家族性AD病例和2000个人群对照进行基于基因的突变负荷病例对照研究。最后，为了便于验证我们的发现，我们将把序列信息存储在公共数据库中。识别新的AD基因将是朝着增加对AD遗传结构的理解迈出的重要一步。这些基因将使诊断试验的发展成为可能，并涉及新的或扩展的涉及AD发病机制的分子途径。对这些途径的研究可能会发现更多的治疗靶点。这项研究还将建立我们的创新分析方法与外显子组测序相结合的实用性，作为鉴定孟德尔常见遗传异质性疾病的基因的有力方法。