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）：虽然已经确定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基因的突变涉及少数AD家族，并以早期发病为特征。大的全基因组关联研究没有发现强有力的证据证明除了APOE基因以外的常见变异的贡献。虽然许多家系提示常染色体显性遗传已被描述和连锁研究发现多个贡献位点的证据，没有新的基因已被确定在过去的20年。该提案的目标是应用新的分析方法来确定AD可能具有单基因病因的家族，并利用下一代测序技术来找到这些基因。华盛顿大学（UW）AD收集了20多个家系，其谱系与孟德尔遗传一致。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龄化研究所（NIA）和国家精神卫生研究所（NIMH）AD收集超过700个家庭。在这些集合中，其中广泛的基因型数据是可用的，我们将进行分段身份的血统（IBD）映射和纯合性的血统（HBD）分析，以检测家庭，共享一个共同的祖先在过去的三到九代。鉴于先证者的确定是基于疾病状态，预计这些分析揭示的相关性反映了从最近的共同祖先遗传的共享因果突变。为了鉴定具有家系的UW家族以及共享IBD和HBD分析所定义的最近祖先的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平行测序，然后进行生物信息学分析和共分离评价。为了确定已识别候选基因与AD的关联，我们将对200多例家族性AD病例和2，000名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，我们将存款序列信息在一个公共数据库。新的AD基因的鉴定将是对AD遗传结构理解的重要一步。这些基因将使诊断测试的发展，并牵连新的或扩展的分子途径参与AD发病机制。对这些途径的检查可能会发现其他治疗靶点。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，作为一种强大的方法，用于识别常见遗传异质性疾病的孟德尔形式的基因。