Allele-specific Mapping in Alzheimer's Disease

阿尔茨海默病的等位基因特异性作图

• 批准号: 8286216
• 负责人: RICHARD P MAYEUX
• 金额: $ 12.8万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8286216
• 关键词: Accounting; Affect; Age; Alleles; Alzheimer' s Disease; Animal Model; Base Sequence; Biological; Biological Assay; Brain; Candidate Disease Gene; Caribbean region; Cell Line; Cerebral cortex; Chromosome Mapping; Chromosomes; Clinical; Code; Communities; Complementary DNA; Complex; Copy Number Polymorphism; DNA; DNA Methylation; DNA Sequence; Data; Data Set; Degenerative Disorder; Dementia; Dependence; Disease; Disease susceptibility; Epigenetic Process; Etiology; Family; Future; Gene Expression; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genome Scan; Genomics; Genotype; Haplotypes; Hereditary Disease; Heritability; Heterozygote; Hispanics; Human; Human Genetics; Individual Differences; Late Onset Alzheimer Disease; Location; Maps; Memory; Methods; Methylation; Molecular; Neurons; Participant; Pathogenesis; Predisposition; Primer Extension; Problem Solving; Research; SNP genotyping; Sampling; Scanning; Series; Signal Transduction; Single Nucleotide Polymorphism in Regulatory Sequence; Surveys; Susceptibility Gene; Testing; Tissues; Variant; age related; base; bisulfite; brain cell; case control; cohort; cost efficient; endophenotype; genetic association; genetic variant; genome wide association study; genome-wide; mRNA Expression; novel strategies; public health relevance; therapeutic target

DESCRIPTION (provided by applicant): Much prior emphasis in research on Alzheimer's disease (AD) has been on genetic studies, which have uncovered the fundamental involvement of the APP, APOE and PS1 genes. But with the exception of polymorphisms in APOE, known coding variants in these genes are quite rare, and the existing data do not fully account for the heritability of late-onset AD (LOAD) in the general population. Additional chromosomal loci putatively influencing AD susceptibility have been uncovered by genome-wide association studies (GWAS) and related high-throughput genomic scans, but replication has been uneven and the causative or predisposing genes have not been clearly pinpointed. Further it has not been possible to gauge the importance of numerous sub-threshold statistical peaks in these scans. New approaches are needed to get through these roadblocks, and we believe that a combined strategy to first obtain lists of loci with sequence-dependent allele-specific methylation (ASM) and/or allele-specific mRNA expression (ASE) in human cerebral cortex, and then overlap this information with statistical peaks from GWAS, will help to solve this problem. We will screen for ASM/ASE in human cerebral cortex using microarray-based and sequencing-based methods. We will validate the strongest candidate loci for ASM/ASE using independent assays, and overlap the list of such loci with data from existing and ongoing GWAS in LOAD. Loci from the intersection of these 2 datasets will be subjected to highly focused and thus cost efficient genetic fine mapping in 3 independent well characterized cohorts of LOAD case and controls. Our reasoning is that sequence-dependent ASM/ASE in or near specific genes in the cerebral cortex will be a robust indicator for the presence of bona fide cis-acting regulatory polymorphisms (rSNPs, rCNPs) that confer inter-individual differences in the expression of specific genes in the human cerebral cortex, and that within this set of genes will be some that cause inter-individual differences in LOAD susceptibility. Reproducible signals from GWAS and related genome scans for LOAD that overlap with loci that show ASM and/or ASE will thus have a strong functional underpinning and warrant further intensive study as biological contributors and potential therapeutic targets in LOAD. PUBLIC HEALTH RELEVANCE: Our project is a combined genetic and epigenetic approach to understand the pathogenesis of Alzheimer's disease (AD), a degenerative disorder of neurons that is the most common cause of age-related dementia. We will use microarray-based and sequencing-based methods to identify the set of genes with genetically determined inter-individual differences in DNA methylation and RNA expression in the human brain. We will overlay this list of genes with lists of AD susceptibility candidate genes that are now emerging from genome- wide association studies (GWAS), and we will carry out fine mapping of the genes and chromosomal regions that score positively in both types of data. By this strategy we expect to be able to more confidently identify genes that affect susceptibility to AD.

描述(由申请人提供)：在阿尔茨海默病(AD)的研究中，大部分先前的重点都在基因研究上，这些研究发现了APP、APOE和PS1基因的基本参与。但除了APOE基因的多态性外，这些基因中已知的编码变异是相当罕见的，现有的数据并不能完全解释迟发性AD(LOAD)在普通人群中的遗传性。全基因组关联研究和相关的高通量基因组扫描已经发现了其他可能影响AD易感性的染色体位点，但复制一直不均衡，致病或易感基因尚未明确定位。此外，还不可能衡量这些扫描中许多低于阈值的统计峰值的重要性。需要新的方法来克服这些障碍，我们相信，首先获得人类大脑皮层中具有序列依赖的等位基因特异性甲基化(ASM)和/或等位基因特异性mRNA表达(ASE)的基因座列表，然后将这些信息与GWAS的统计峰值重叠，将有助于解决这个问题。我们将使用基于微阵列和基于测序的方法在人类大脑皮层中筛选ASM/ASE。我们将使用独立的分析来验证ASM/ASE最强的候选基因座，并将这些基因座的列表与现有的和正在进行的GWALOAD中的数据重叠。来自这两个数据集的交集的基因座将在3个独立的、特征良好的负荷病例和对照队列中进行高度聚焦和成本效益高的遗传精细定位。我们的推理是，大脑皮层特定基因中或其附近的序列依赖的ASM/ASE将是存在真正的顺式调节多态(rSNPs，rCNPs)的一个强有力的指标，这些多态导致人类大脑皮层特定基因的表达存在个体间的差异，而在这组基因中，将有一些基因导致个体间负载易感性的差异。因此，来自GWAS和相关基因组扫描的可重现的信号与显示ASM和/或ASE的基因座重叠的LOAD将具有强大的功能支持，并值得进一步深入研究LOAD中的生物贡献者和潜在的治疗靶点。 公共卫生相关性：我们的项目是采用遗传学和表观遗传学相结合的方法来了解阿尔茨海默病(AD)的发病机制，AD是一种神经元退行性疾病，是导致老年性痴呆的最常见原因。我们将使用基于微阵列和基于测序的方法来识别在人脑中具有遗传决定的DNA甲基化和RNA表达的个体间差异的基因集。我们将在这个基因列表上叠加目前从全基因组关联研究(Gwas)中出现的AD易感候选基因列表，并对在两种类型的数据中得分均为阳性的基因和染色体区域进行精细定位。通过这一策略，我们希望能够更有信心地识别影响AD易感性的基因。