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

抽象的。拉美裔/拉丁裔(“HL”，欧洲[欧盟]、非洲[AF]和美洲原住民的基因混血) [NA]血统)表明阿尔茨海默病(AD)的患病率和发病率高于非西班牙裔 白色的。在美国，HL和其他混合群体的数量仍然不足以提供统计数据 在识别危险和保护性遗传变异方面的重要意义，特别是在罕见的情况下。为此，我们介绍了我们的 研究：AD的全球拉丁裔测序研究(“Glass-AD”)。我们将做出贡献，创造必要的 AD表型HL中发现稀有变异体(RV)的数量。我们的建议回应了 阿尔茨海默病测序项目(ADSP)后续研究2.0(PAR 21-212)FOA，敦促确保 通过利用现有的队列和/或在阿尔茨海默病的遗传学研究中适当代表不同的人群 计划新的招聘，以获得足够的样本数量和权力。在这项研究中，我们将生成新的整体 6,000例HL：N=4,000的基因组测序数据(WGS)是我们最近资助的研究的一部分 在ADSP中保留阿尔茨海默病多样性遗传队列“(ReadD-ADSP AG074865)和 N=2 000名来自秘鲁和玻利维亚的新征聘人员，利用已建立的两人当地网络 正在进行的招聘研究(R56AG069118；R01AG070864)。Glass-AD与其他独立的HL 队列，最终将为我们提供一大组具有广泛血统比例的个体，特别是 NA血统(加勒比拉美裔占8%，墨西哥裔占50%，秘鲁混血族占70%，秘鲁占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，因为与占主导地位的样本相比，目前代表不足 非洲血统(例如，非洲裔美国人、加勒比拉美裔美国人)。除了新的招聘和WGS数据外， 我们将i)产生AD生物标记物(Aβ42、tau蛋白等)。在2,000名秘鲁人/玻利维亚人和二)开展 GRASS-AD招募的健康对照和轻度认知障碍患者子集的随访 秘鲁/玻利维亚(N=1,000)和ReadD-ADSP(N=1,000)在初次就诊后的3年内评估临床进展。 我们还将阐明AD与收集的风险因素(认知、健康状况和 行为，血液生物标志物)横向和纵向，并执行传统和创新的房车 分析。玻璃-AD与主要的ADSP财团完全整合：样品将存放在国家 阿尔茨海默病细胞库(NCRAD)，遗传数据将受到质量控制和协调 遵循NIA Genetics保存和共享的阿尔茨海默病基因组中心(GCAD)指南 阿尔茨海默病数据存储网站(NIAGADS)。玻璃数据将与ADSP后续研究共享 (“FUS”AG057659、AG062943和AG076482)，它正在对几个独立的HL队列进行测序，并将 确保使用WGS数据收集最大的HL。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组织[CARRE])。

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]).