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）：尽管众所周知，家族性阿尔茨海默氏病（AD）具有很强的遗传基础，但额外的孟德尔基因仍有待鉴定。应用程序中的突变，PSEN1或PSEN2基因参与少数AD家族，并以早期疾病发作为特征。大型基因组关联研究尚未发现除APOE基因以外的常见变体的贡献的有力证据。尽管许多具有谱系的家族暗示了常染色体显性遗传，并且连锁研究发现了多个贡献基因座的证据，但在过去20年中，未发现新基因。该提案的目的是采用新颖的分析方法来识别AD可能具有单一基因病因的家庭，并利用下一代测序技术来找到这些基因。华盛顿大学（UW）广告系列包含二十多个家庭，其中血统与门德尔的继承一致。为了确定单个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化研究所（NIA）和国家心理健康研究所（NIMH）AD收集，拥有700多个家庭。在这些收藏集中，为此可获得广泛的基因型数据，我们将执行分段性的逐个映射（IBD）映射和纯合性划分（HBD）分析（HBD）分析，以检测过去三到九代共同祖先的家庭。鉴于基于疾病状况的检验的确定，预计这些分析发现的相关性反映了最近共同祖先共享的因果突变的遗传。为了鉴定具有谱系的UW家族中的候选基因，以及由IBD和HBD分析定义的NIA和NIMH家族，我们将进行外显群捕获和大量平行测序，然后进行生物信息学分析以及对共脱粒化的评估。为了建立已鉴定的候选基因与AD的关联，我们将使用200多个家庭AD病例和2,000个种群对照进行基于基因的突变载荷病例对照研究。最后，为了促进验证我们的发现，我们将将序列信息存储在公共数据库中。新型AD基因的鉴定将是对AD遗传结构的增强理解的重要一步。这些基因将能够开发诊断测试，并暗示与AD发病机理有关的新的或扩展的分子途径。对这些途径的检查可能会揭示其他治疗靶标。这项研究还将建立我们创新的分析方法与外显子组测序相结合的实用性，作为鉴定孟德尔形式的常见遗传性异构疾病的基因的有力方法。 公共卫生相关性：拟议的研究与公共卫生具有重要意义。阿尔茨海默氏病（AD）在70岁时影响5％的个体，是美国老年人口发病率和死亡率的主要原因。它构成了重大的家庭和社会负担。一些疾病进展减慢的药物可用，但没有已知的预防或治疗方法。 AD具有很大的遗传贡献，尽管已知一些单个基因亚型，但仍有更多的AD基因。该提案的目的是发现新颖的AD单基因原因。鉴定AD中涉及的新基因和途径将为改进诊断和治疗策略提供基础。 。