Sequence-based Discovery of AD Risk & Protective Alleles

描述(由申请人提供)：这个序列分析联盟(SAC)汇集了阿尔茨海默病(AD)、人类遗传学、生物统计学和基因组科学方面的专家，以确定影响AD和AD相关内表型的风险和保护性单核苷酸和拷贝数变体(SNV和CNV)。该SAC将协调和整合AD测序项目(ADSP)和其他数据资源中的基因组和表型数据(由核心C生成)，并使用最具信息量的分析方法(由核心B确定)来识别新的风险和保护性等位基因。这项SAC部分基于ADSP病例对照研究设计，在6888例患者中进行了完整的外显子组测序，这些患者尽管先天风险较低，但仍发展为AD，并可能富含新的风险变量，以及14,400名认知正常的老年对照组，其中一部分富含保护性变量。为了在携带不成比例AD负担的少数群体中进行新的发现，我们将分析外显子序列数据和特征良好的内表型，包括言语记忆和海马体体积(由核心D协调)。复制将使用在50,000个病例和对照以及40,000个具有内表型数据的个体中的目标序列和基因数据来提供。我们将寻求确定有助于AD易感性和保护的SNV(项目1)和CNV(项目2)。综合和注释(使用ENCODE和表观基因组路线图项目)来自ADSP家族的SNV和CNVS数据，以及其他家族性AD资源，将用于遗传连锁和IBD分析(项目3)，以在高度确定的多基因家族中识别AD易感性或保护性等位基因。病例对照设计(项目1和2)和家族设计(项目3)相辅相成，以最大限度地发现AD变异。为了促进AD的翻译研究和发现，我们将与其他研究人员合作，进行进一步的复制和功能研究，利用整合的基因组和表型数据创建公共资源，并通过公共领域提供计算算法。识别导致阿尔茨海默病风险和保护AD的基因变异可能最终导致新的治疗和预防策略。

DESCRIPTION (provided by applicant): This Sequence Analysis Consortium (SAC) brings together experts in Alzheimer's disease (AD), human genetics, biostatistics and genome sciences to identify risk and protective single nucleotide and copy number variants (SNVs and CNVs) influencing AD and AD-related endophenotypes. This SAC will harmonize and integrate genomic and phenotype data (generated by Core C) from the AD Sequencing Project (ADSP) and other data resources and use the most informative analytic methods (as determined by Core B) to identify novel risk and protective alleles. This SAC is partially based on the ADSP case-control study design with whole exome sequencing in 6,888 cases who developed AD despite an 'a priori low risk' and are likely enriched for novel risk variants, and 14,400 cognitivly normal older controls, a subset of whom are enriched for protective variants. To allow novel discovery in minority populations that carry a disproportionate burden of AD, we will analyze exome sequence data and well-characterized endophenotypes, including verbal memory and hippocampal volume (harmonized by Core D). Replication will be afforded using targeted sequence and genotype data in 50,000 cases and controls and 40,000 individuals with endophenotype data. We will seek to identify SNVs (Project 1) and CNVs (Project 2) contributing to AD susceptibility and protection. Integrated and annotated (using ENCODE and the Epigenomic Roadmap Projects) SNVs and CNVs data from the ADSP families with whole genome sequencing, as well as other familial AD resources will be used for genetic linkage and IBD analyses (Project 3) to identify AD susceptibility or protective alleles in highly-ascertained, multiplex families. The case-control design (Projects 1 and 2) and the family design (Project 3) complement each other to maximize discovery of AD variants. In order to promote AD translational research and discovery, we will collaborate with other researchers to undertake further replication and functional studies, create public resources with integrated genomic and phenotypic data, and make available computational algorithms through the public domain. Identification of variants in genes leading to risk and protection from AD may ultimately lead to novel treatments and prevention strategies.