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: 8721824
• 负责人: M. Ilyas Kamboh
• 金额: $ 61.65万
• 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/8721824
• 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; 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; genetic variant; genome wide association study; next generation sequencing; public health relevance; rare variant; 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）：阿尔茨海默病（AD），特别是晚发性（LOAD）是一种复杂的多因素神经退行性疾病，可能涉及多个基因。直到2010年，APOE是LOAD的唯一确定的危险因素。然而，最近的五项大型全基因组关联研究（GWAS）发现，LOAD与另外9个位点的SNPs存在显著关联，包括ABCA7、MS4A4、EPHA1、CLU、CR1、PICALM、BIN1、CD2AP和CD33，以及除CR1和CD2AP外的所有位点，在GWAS样本中都得到了重复。尽管GWAS在发现LOAD的其他基因方面做出了重大贡献，但它们不太可能确定所有的遗传贡献，因为商业GWAS阵列的设计仅捕获具有低外显率的常见变异，以测试常见疾病/常见变异假设。另一方面，与未被GWAS捕获的常见变异相比，个体外显率更高的罕见变异可能占常见和复杂疾病的人群归因风险的1/3，多种罕见变异可能占许多观察到的GWAS信号。此外，GWAS阵列使用依赖于链接不平衡的间接关联方法来检测关联信号，并且很少识别出显著变异