Search for the Alzheimers Genes

 描述(由申请人提供)：本次竞争性续签申请旨在继续阿尔茨海默病(AD)遗传学研究项目。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关联研究，作为国内和国际合作的一部分，这有助于识别AD的多个新基因座。除了GWAS，我们还对候选基因进行了几项关联研究，这些研究在当前的赠款期间发表了50篇论文。使用病例对照关联设计确定的AD风险确认基因仅占表型变异的约30%。另一种侧重于AD定量表型/内表型的方法可能有助于确定AD的其他基因，因为这种方法可能比使用二元病例对照设计更有效。作为此次更新的初步数据的一部分，我们完成了对四种与AD相关的表型的GWAS：通过淀粉样成像测量大脑中Aü的沉积，通过12个月的简易精神状态检查(MMSE)分数的变化测量短期疾病进展，通过达到MMSE 9分数的时间测量疾病进展(中到重度AD的指标)，以及在AD中的生存时间。我们已经为每个AD相关表型确定了新的基因座。利用通路分析，我们还在GWAS相关的基因网络中确定了多个潜在的新候选基因。由于Gwas阵列使用一种依赖于连锁不平衡来检测关联信号的间接方法，因此被识别的显著变异很少是因果变异。在清华大学，重要的是对GWAS涉及的候选基因区域和参与其网络的基因区域进行重新测序，以表征与AD相关表型相关的常见、低频和罕见原因变异的全谱。这一更新应用的目的是对GWAS涉及的选定顶端基因区域和GWAS相关基因网络中的其他候选基因进行有针对性的重新测序，以确定与四种AD相关表型相关的因果变异。将在独立的复制样本集中寻找在发现阶段获得的重要变异的复制。最后，我们将使用生物信息学工具和脑基因表达数据来检查已识别的显著变体的功能性质。拟议的全面研究的成功完成将可能导致识别与AD相关的新基因/变种。

 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.