GLASS-AD: Global Latinos Sequencing Study for Alzheimer's Disease

摘要。西班牙裔/拉丁裔（“HL”，欧洲人[EU]、非洲人[AF]和美洲原住民的基因混合 [NA]与非西班牙裔相比， 白人美国的HL和其他混合组的数量仍不足以提供统计学 在识别风险和保护性遗传变异方面具有重要意义，特别是在罕见的情况下。为此，我们介绍我们的 研究：AD的全球LAtinos测序研究（“GLASS-AD”）。我们将致力于创造必要的 在AD表型分型的HL中发现的罕见变体（RV）数量。我们的建议回应了 阿尔茨海默病测序项目（ADSP）随访研究2.0（PAR 21-212）FOA，敦促确保 通过利用现有队列，在AD遗传研究中适当代表不同人群，和/或 计划新的招募，以获得足够的样本量和把握度。在这项研究中，我们将产生新的整体 6，000例HL的基因组测序数据（WGS）：N= 4，000，作为我们最近资助的研究“招募和 ADSP中阿尔茨海默病多样性遗传队列的保留”（READD-ADSP AG 074865）和 N= 2 000名来自秘鲁和玻利维亚的新征聘人员，利用现有的两个地方网络 正在进行的招募研究（R56 AG 069118; R 01 AG 070864）。GLASS-AD与其他独立HL 队列，最终将为我们提供一个大的一组具有广泛的祖先比例，特别是 NA血统（加勒比海西班牙裔8%，墨西哥裔约50%，秘鲁混血70%，秘鲁混血>90%） 和玻利维亚土著群体）。重要的是，我们将增加样本的代表性， NA血统，这是必要的，因为目前代表性不足相比，样本占主导地位 非洲血统（例如，非洲裔美国人，加勒比海西班牙裔）。除了新的招聘和WGS数据， 我们将I）产生AD-生物标志物（Aβ42、tau蛋白等）在2 000名秘鲁人/玻利维亚人中， 在GLASS-AD招募的健康对照和轻度认知障碍的亚组中进行随访， 秘鲁/玻利维亚（N= 1，000）和READD-ADSP（N= 1，000）在初次访视后约3年时评估临床进展。 我们还将阐明AD与收集的危险因素（认知、健康状况和 行为，血液生物标志物），并执行传统和创新的RV 分析。GLASS-AD与主要的ADSP财团完全整合：样品将存放在国家实验室。 阿尔茨海默病细胞库（NCRAD），遗传数据将得到质量控制和协调 根据阿尔茨海默病基因组中心（GCAD）指南，由NIA Genetics保存和共享， 阿尔茨海默病数据存储网站（NIAGADS）。GLASS数据将与ADSP随访研究共享 （“FUS”AG 057659、AG 062943和AG 076482），其正在对几个独立的HL队列进行测序，并将 确保HL与WGS数据的最大收集。重要的是，我们的分析方法将与 正在进行的ADSP分析联盟（例如，阿尔茨海默病研究合作[CADRE]）。

ABSTRACT. Hispanics/Latinos (“HL”, genetically admixed of European [EU], African [AF] and Native American [NA] ancestry) show higher prevalence and incidence of Alzheimer's disease (AD) compared to non-Hispanic Whites. Numbers of HL and other admixed groups in the US remain insufficient to provide statistical significance in identifying risky and protective genetic variants, especially if rare. To this end, we introduce our study: Global LAtinos Sequencing Study for AD (“GLASS-AD”). We will contribute to generate necessary numbers for rare variants (RV) discovery in HL phenotyped for AD. Our proposal responds to the Alzheimer’s Disease Sequencing Project (ADSP) Follow-Up Study 2.0 (PAR 21-212) FOA, which urges to ensure appropriate representation of diverse populations in genetic studies of AD by leveraging existing cohorts and/or planning new recruitment to obtain sufficient sample sizes and power. In this study we will generate new whole genome sequencing data (WGS) in 6,000 HL: N=4,000 as part of our recently funded study “Recruitment and Retention for Alzheimer's Disease Diversity Genetic Cohorts in the ADSP” (READD-ADSP AG074865) and N=2,000 newly recruited individuals from Peru and Bolivia, leveraging the established local networks of two ongoing recruitment studies (R56AG069118; R01AG070864). GLASS-AD, together with other independent HL cohorts, will ultimately provide us with a large set of individuals with wide range of ancestry proportion, particularly for NA ancestry (8% in Caribbean Hispanics, ~50% in Mexicans, 70% in Peruvian mestizos, >90% in Peruvian and Bolivian indigenous groups). Importantly, we will increase representation of samples with substantial NA ancestry, which are needed because currently underrepresented compared to samples with predominant African ancestry (e.g., African Americans, Caribbean Hispanics). In addition to new recruitment and WGS data, we will I) generate AD-biomarkers (Aβ42, tau proteins etc.) in the 2,000 Peruvians/Bolivians and II) conduct a follow-up visit in a subset of healthy controls and mild cognitive impairment recruited by GLASS-AD in Peru/Bolivia (N=1,000) and READD-ADSP (N=1,000) at ~3 years from initial visit to assess clinical progress. We will also elucidate the association between AD and collected risk factors (cognition, health conditions and behaviors, blood biomarkers) cross-sectionally and longitudinally and perform traditional and innovative RV analyses. GLASS-AD is fully integrated with major ADSP consortia: samples will be deposited at the National Cell Repository for Alzheimer's Disease (NCRAD), genetic data will be quality controlled and harmonized following Genome Center for Alzheimer's Disease (GCAD) guidelines, deposited and shared by NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS). GLASS data will be shared with the ADSP Follow-Up Study (“FUS” AG057659, AG062943 and AG076482), which is sequencing several independent HL cohorts and will ensure the largest collection of HL with WGS data. Importantly, our analyses methods will be harmonized with ongoing ADSP analyses consortia (e.g. Collaborative for Alzheimer’s Disease Research [CADRE]).