Deep Resequencing of Candidate Gene Regions in Late-onset Alzheimer's Disease

晚发性阿尔茨海默病候选基因区域的深度重测序

• 批准号: 8554751
• 负责人: M. Ilyas Kamboh
• 金额: $ 58.49万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8554751
• 关键词: Accounting; Affect; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Apolipoprotein E; Biological; Brain; Candidate Disease Gene; Cerebellum; Complex; DNA Resequencing; Data; Dementia; Disease; EPHA1 gene; Elderly; Environmental Risk Factor; Family; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genotype; Goals; Human; Individual; Intercistronic Region; Introns; Joints; Late Onset Alzheimer Disease; Linkage Disequilibrium; Measures; Medical; Modeling; Neurodegenerative Disorders; PTK2B gene; Penetrance; Phenotype; Population Attributable Risks; Predisposition; Prefrontal Cortex; Public Health; Reporting; Research; Risk; Risk Factors; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Staging; Structure; Temporal Lobe; Testing; Universities; Untranslated Regions; Variant; apolipoprotein E-4; case control; design; disorder risk; functional group; genome wide association study; next generation sequencing; public health relevance; trait

DESCRIPTION (provided by applicant): Alzheimer's disease (AD), especially late-onset (LOAD) is a complex multifactorial neurodegenerative disease with the possible involvement of several genes. Until 2010, APOE was the only established risk factor for LOAD. However, recent five large genomewide association studies (GWAS) have identified significant associations of LOAD with SNPs in nine additional loci, including, ABCA7, MS4A4, EPHA1, CLU, CR1, PICALM, BIN1, CD2AP and CD33 and all, but CR1 and CD2AP, have been replicated in our GWAS sample. Although GWAS have made significant contribution in uncovering additional genes for LOAD, they are unlikely to identify all the genetic contribution because the commercial GWAS arrays are designed to capture only the common variants with low penetrance to test common disease/common variant hypothesis. On the other hand, rare variants having a higher individual penetrance than common variants that are not captured by GWAS may account for 1/3 of the population attributable risk for common and complex diseases and multiple rare variants may account for many of the observed GWAS signals. Furthermore, GWAS arrays use an indirect approach of association that relies on linkage disequilibrium to detect association signals and rarely the identified significant variants are the causal variants. This may explain the small effect sizes associated with the observed GWAS signals. Here we propose to perform deep resequencing of the seven gene regions implicated in recent GWAS and replicated in our sample and selected additional genes involved in the networks of these seven genes using next-generation sequencing in 1,000 AD cases and controls to identify both common and rare SNPs and replicate them in independent samples. The identification of causal variants in these genes would make a significant contribution in understanding the underlying biological mechanism of LOAD.

描述（由申请人提供）：阿尔茨海默氏病（AD），尤其是晚期（载荷）是一种复杂的多因素神经退行性疾病，可能会参与多种基因。直到2010年，APOE是负载唯一确定的风险因素。然而，最近的五项全基因组关联研究（GWAS）已经确定了在九个其他基因座中的SNP的显着关联，包括ABCA7，MS4A4，EPHA1，EPHA1，CLU，CR1，PICALM，PICALM，BIN1，CD2AP和CD33和CD33以及所有，但是CR1和CD2AP在我们的GWAS样本中已复制。尽管GWAS在发现额外的载荷基因方面做出了重大贡献，但它们不太可能识别所有遗传贡献，因为商业GWAS阵列旨在仅捕获具有低渗透率的常见变体来检验常见疾病/常见变体假设。另一方面，与GWA未捕获的常见变体相比，具有更高个性变体的稀有变体可能占常见和复杂疾病的可归因于可造成的人群风险，并且多种稀有变体可能会解释许多观察到的GWAS信号。此外，GWAS阵列采用间接的关联方法，该方法依赖于连锁不平衡来检测关联信号，并且很少确定的重要变体是 因果变体。这可以解释与观察到的GWAS信号相关的小效应大小。在这里，我们建议对与最近的GWAS有关的七个基因区域进行深度重新配置，并在我们的样品中复制，并在1,000例AD病例中使用下一代测序涉及这七个基因网络的其他基因，以识别常见和稀有SNP并在独立样品中复制它们。这些基因中因果变异的鉴定将在理解负载的潜在生物学机制方面做出重大贡献。