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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：虽然众所周知，家族性阿尔茨海默病（AD）具有强大的遗传基础，但其他孟德尔基因仍有待鉴定。 APP、PSEN1 或 PSEN2 基因突变涉及少数 AD 家族，其特征是疾病早期发作。大型全基因组关联研究尚未发现除 APOE 基因外常见变异的贡献的有力证据。尽管许多谱系暗示常染色体显性遗传的家族已被描述，并且连锁研究也发现了多个贡献位点的证据，但在过去 20 年中尚未发现新的基因。该提案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族，并利用下一代测序技术来查找这些基因。华盛顿大学 (UW) AD 收藏包含 20 多个谱系符合孟德尔遗传的家族。为了确定单基因可能造成因果关系的其他家族，我们将使用现有的、经过充分表征的国家老龄化研究所 (NIA) 和国家心理健康研究所 (NIMH) AD 集合，其中包含 700 多个家庭。在这些拥有大量基因型数据的集合中，我们将进行分段的血统同一性 (IBD) 作图和血统纯合性 (HBD) 分析，以检测在过去三到九代内拥有共同祖先的家族。鉴于根据疾病状况确定先证者，预计这些分析揭示的相关性反映了来自最近共同祖先的共同因果突变的遗传。为了识别具有谱系的 UW 家族以及具有 IBD 和 HBD 分析定义的近期血统的 NIA 和 NIMH 家族中的候选基因，我们将进行外显子组捕获和大规模并行测序，然后进行生物信息学分析和共分离评估。为了建立已确定的候选基因与 AD 的关联，我们将对 200 多个家族性 AD 病例和 2,000 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放在公共数据库中。新 AD 基因的鉴定将是加深对 AD 遗传结构了解的重要一步。这些基因将使诊断测试的发展成为可能，并暗示参与 AD 发病机制的新的或扩展的分子途径。对这些途径的检查可能会揭示更多的治疗靶点。这项研究还将确立我们的创新分析方法与外显子组测序相结合的效用，作为识别孟德尔形式常见遗传异质性疾病基因的强大方法。