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: 8082408
• 负责人: Zoran Brkanac
• 金额: $ 61.67万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8082408
• 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; familial Alzheimer disease; genetic pedigree; genome wide association study; improved; in vitro Model; innovation; mortality; next generation; 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. PUBLIC HEALTH RELEVANCE: The proposed research has major relevance for public health. Alzheimer disease (AD) affects 5% of individuals by age 70 and is a leading cause of morbidity and mortality in the aging US population. It constitutes a significant familial and societal burden. Some medications that slow the progression of disease are available, but there are no known preventions or cures. AD has a substantial genetic contribution and although some single gene subtypes are known, more AD genes remain to be found. The goal of this proposal is to discover novel single gene causes of AD. The identification of new genes and pathways involved in AD will provide a foundation for improved diagnostic and therapeutic strategies. .

描述（由申请人提供）：虽然家族性阿尔茨海默病（AD）具有很强的遗传基础，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，并以疾病早期发病为特征。大型全基因组关联研究没有发现强有力的证据表明，除了APOE基因外，常见变异也有贡献。虽然许多家庭的家谱暗示常染色体显性遗传已经被描述，连锁研究已经发现了多个贡献位点的证据，但在过去的20年里没有发现新的基因。本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寻找这些基因。华盛顿大学（UW） AD收藏了20多个家庭，他们的血统与孟德尔遗传一致。为了确定单基因可能是因果关系的其他家庭，我们将使用现有的、具有良好特征的国家老龄化研究所（NIA）和国家精神卫生研究所（NIMH）收集的700多个家庭的AD。在这些可获得广泛基因型数据的集合中，我们将进行分段血统识别（IBD）图谱和血统纯合子（HBD）分析，以检测在过去3至9代内拥有共同祖先的家族。鉴于基于疾病状态的先证的确定，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。为了确定UW家族的候选基因，以及由IBD和HBD分析定义的具有最近祖先的NIA和NIMH家族的候选基因，我们将进行外显子组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。为了确定已确定的候选基因与AD的关联，我们将对200多例家族性AD病例和2000例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。新的阿尔茨海默病基因的鉴定将是对阿尔茨海默病遗传结构理解的重要一步。这些基因将促进诊断测试的发展，并暗示涉及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。这项研究还将建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的常见遗传异质性疾病的基因的有力方法。