Search for the Alzheimers Genes

 描述（由申请人提供）：这个竞争性的续期申请旨在继续对阿尔茨海默病（AD）的遗传学项目。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（GWAS），作为国家和国际合作的一部分，该研究有助于识别AD的多个新位点。除了GWAS，我们还对候选基因进行了几项关联研究，在本资助期内发表了超过50篇论文。使用病例对照关联设计确定的AD风险的确认位点仅占表型方差的约30%。一种专注于AD定量表型/内表型的替代方法可能有助于识别AD的其他基因，因为这种方法比使用二元病例对照设计更有效。作为我们此次更新的初步数据的一部分，我们已经完成了四种AD相关表型的GWAS：通过淀粉样蛋白成像测量的大脑中的Ablation沉积，通过12个月内的简易精神状态检查（MMSE）评分变化测量的短期疾病进展，通过达到MMSE 9评分（中度至重度AD的指标）的时间测量的疾病进展，以及AD的生存时间。我们已经确定了每个AD相关表型的新基因座。使用途径分析，我们还确定了多个潜在的新的候选基因在网络中的GWAS牵连的基因。由于GWAS阵列使用依赖于连锁不平衡的间接方法来检测关联信号，因此所鉴定的显著变异很少是因果变异。因此，重要的是对GWAS所涉及的候选基因区域以及参与其网络的候选基因区域进行重新测序，以表征与AD相关表型相关的常见、低频和罕见致病变异的全谱。该更新申请的目的是对GWAS涉及的选定顶级基因区域和GWAS涉及的基因网络中的其他候选基因进行靶向重测序，以鉴定与四种AD相关表型相关的致病变体。将在独立的复制样品组中寻找在发现阶段获得的重要变体的复制。最后，我们将使用生物信息学工具和大脑基因表达数据来研究所识别的重要变体的功能性质。成功完成拟议的全面研究可能会导致识别新的AD相关基因/变体。

 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.