Allele-specific Mapping in Alzheimer's Disease

描述（由申请人提供）：在阿尔茨海默病（AD）的研究中，许多先前的重点放在基因研究上，这些研究已经揭示了APP， APOE和PS1基因的基本参与。但是，除了APOE的多态性外，已知的这些基因的编码变异相当罕见，现有的数据并不能完全解释晚发型AD （LOAD）在普通人群中的遗传性。全基因组关联研究（GWAS）和相关的高通量基因组扫描发现了其他可能影响阿尔茨海默病易感性的染色体位点，但复制不均匀，致病或易感基因尚未明确确定。此外，还不可能衡量这些扫描中许多次阈值统计峰值的重要性。需要新的方法来克服这些障碍，我们认为，首先获得人类大脑皮层中序列依赖性等位基因特异性甲基化（ASM）和/或等位基因特异性mRNA表达（ASE）的位点列表，然后将这些信息与GWAS的统计峰重叠，将有助于解决这一问题。我们将使用基于微阵列和基于测序的方法筛选人类大脑皮层中的ASM/ASE。我们将使用独立分析验证ASM/ASE最强候选基因座，并将这些基因座列表与LOAD中现有和正在进行的GWAS数据重叠。来自这两个数据集交叉点的基因座将在LOAD病例和对照的3个独立的、具有良好特征的队列中进行高度集中的、因此具有成本效益的遗传精细定位。我们的推理是，大脑皮层中特定基因或其附近的序列依赖性ASM/ASE将是一个强有力的指标，表明真正的顺式作用调节多态性（rsnp, rCNPs）的存在，这些多态性赋予人类大脑皮层中特定基因表达的个体差异，并且在这组基因中将存在一些导致LOAD易感性的个体差异。因此，来自GWAS和相关基因组扫描的可重复信号与显示ASM和/或ASE的位点重叠，将具有强大的功能基础，值得进一步深入研究，作为LOAD的生物学贡献因子和潜在治疗靶点。

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.