Search for the Alzheimers Genes

寻找阿尔茨海默病基因

• 批准号: 9190589
• 负责人: M. Ilyas Kamboh
• 金额: $ 15.4万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190589
• 关键词: Accounting; African American; Age; Alzheimer' s Disease; Alzheimer' s disease risk; American; Amyloid beta-Protein; Bioinformatics; Brain; Candidate Disease Gene; Cerebellum; Collaborations; DNA; DNA Resequencing; Data; Databases; Deposition; Disease; Disease Progression; European; Frequencies; Funding; Gene Expression; Gene Frequency; Genes; Genetic; Genomics; Genotype; Grant; Heritability; Individual; International; Joints; Lead; Linkage Disequilibrium; Measures; Minor; Nature; Pathway Analysis; Patients; Pattern; Penetrance; Pharmacotherapy; Phenotype; Prefrontal Cortex; Public Health; Publications; Publishing; Research; Sampling; Signal Transduction; Staging; Targeted Resequencing; Temporal Lobe; Testing; Time; Universities; Variant; abeta deposition; amyloid imaging; case control; design; effective therapy; endophenotype; exome sequencing; follow-up; genetic variant; genome sequencing; genome wide association study; mental state; model building; novel; phenotypic data; public health relevance; rare variant; targeted sequencing; tool; whole genome

 DESCRIPTION (provided by applicant): This competitive renewal application seeks to continue a project on the genetics of Alzheimer's disease (AD). As part of the funded project we performed genome-wide association study (GWAS) on our case-control sample that has contributed to the identification of multiple novel loci for AD as part of national and internationl collaborations. In addition to GWASs, we also performed several association studies on candidate genes that resulted in >50 publications during the current grant period. Confirmed loci identified for AD risk using the case-control association design account for only ~30% of the phenotypic variance. An alternative approach focusing on AD quantitative phenotypes/endophenotypes may help to identify additional genes for AD, as this approach can be more powerful than using the binary case-control design. As part of our preliminary data for this renewal, we have completed GWASs on four AD-related phenotypes: deposition of Aß in the brain measured by amyloid imaging, short-term disease progression measured by change in Mini-Mental State Examination (MMSE) score over 12 months, disease progression measured by time to reach MMSE 9 score (indicator of moderate to severe AD), and survival time in AD. We have identified novel loci for each AD- related phenotype. Using pathway analysis we have also identified multiple potentially novel candidate genes in the networks of GWAS-implicated genes. Since GWAS arrays use an indirect approach that relies on linkage disequilibrium to detect association signals, rarely are the identified significant variants the causal variants. Thu, it is important to resequence the candidate gene regions implicated by GWASs and those that participate in their networks in order to characterize the full spectrum of common, low-frequency and rare causal variants associated with AD-related phenotypes. The objective of this renewal application is to perform targeted resequencing of selected top gene regions implicated by GWASs and additional candidate genes in the networks of GWAS-implicated genes in order to identify causal variants associated with four AD-related phenotypes. Replication of significant variants obtained in the discovery stage will be sought in independent sets of replication samples. Finally, we will examine the functional nature of the identified significant variants usin bioinformatics tools and brain gene expression data. The successful completion of the proposed comprehensive studies will likely lead to the identification of new AD-related genes/variants.

 描述（由应用程序提供）：此竞争性更新应用程序旨在继续有关阿尔茨海默氏病（AD）的遗传学项目。作为资助项目的一部分，我们对我们的病例对照样本进行了全基因组协会研究（GWAS），该研究已促进了作为国家和国际合作的一部分，为AD的多个新颖地点识别。除GWASS外，我们还对候选基因进行了几项关联研究，这些研究在当前赠款期间导致> 50个出版物。使用病例对照关联设计占表型差异的约30％，确认对AD风险进行了定位。一种关注AD定量表型/内型型的替代方法可能有助于鉴定AD的其他基因，因为这种方法比使用二进制病例对照设计更强大。 As part of our preliminary data for this renewal, we have completed GWASs on four AD-related phenotypes: deposition of Aß in the brain measured by amyloid imaging, short-term disease progression measured by change in Mini-Mental State Examination (MMSE) score over 12 months, disease progression measured by time to reach MMSE 9 score (indicator of moderate to severe AD), and survival time in AD.我们已经确定了每种相关表型的新型位置。使用途径分析，我们还鉴定了GWAS IMPLIFIED基因网络中的多个潜在的新型候选基因。由于GWAS阵列使用依赖链接dissequibrium的间接方法来检测关联信号，因此很少有因果变体所识别的重要变体。 thu，重要的是要重新设备GWASS实施的候选基因区域以及参与其网络的候选基因区域，以表征与与AD相关表型相关的共同，低频和罕见的因果变体。该更新应用的目的是对GWASS实施的选定顶级基因区域和GWASIMPLIFIED基因网络中实施的其他候选基因进行针对性重新方程，以识别与四个与AD相关的表型相关的因果变异。在发现阶段获得的重要变体的复制将在独立的复制样本集中感知。最后，我们将研究确定的重要变体的功能性质USIN生物信息学工具和脑基因表达数据。拟议的综合研究的成功完成可能会导致鉴定新的与广告相关的基因/变体。