Whole genome sequencing of the Mexican Health Aging Study (MHAS) cohort

摘要 我们的目标是对全基因组测序（WGS）数据进行传统和创新的遗传分析 来自墨西哥健康老龄化研究（MHAS）的3，500名参与者的子样本。我们有 已经获得资助，收集唾液进行DNA提取，并在这个基因组中进行全基因组关联研究。 墨西哥样本（授权编号R56-AG 059756，PI：Tosto，Barral，Mayeux）。 越来越多的证据支持一个强大的遗传因素支撑的生理病理学晚发性 阿尔茨海默病（LOAD）。欧洲人口研究仍然主导着现有的基因组数据库 导致调查结果在不同和少数群体中缺乏普遍性。到2020年， 拉丁美洲的痴呆症发病率将增加120%，而北美为49%。因此，关键是 增加西班牙裔和拉丁裔在遗传调查中代表性。墨西哥人目前没有 在对LOAD的大型遗传研究中有代表性。它们显示出独特的遗传特征，具有最高的原住民- 美国祖先成分百分比（约50%）。该人群可能具有独特的LOAD风险/保护性 等位基因，这是罕见的或在其他人群中不存在。此外，它可能揭示了本地的贡献， 这是一个关于LOAD风险的祖先，这仍然是未知的。 到目前为止，我们的研究小组已经收集了9,162份来自60岁及以上的MHAS参与者的唾液和血液样本， 将它们储存在国家阿尔茨海默病细胞库（NCRAD）。MHAS还提供了一套丰富的 表型（人口统计学、认知和医学评估）以及20年随访期。的 将接受全基因组测序的参与者（N~ 3，500名符合痴呆临床标准的参与者， 认知健康;比例1：4）的特征是额外的深入认知评估，我们已经 已经资助。广泛的认知内表型的可用性将促进过多的 超越经典病例对照设计的研究（即生存分析和认知轨迹）;它将 确保LOAD诊断的准确性，并将促进不同测序之间的表型协调 同伙 我们建议：目标1）对产生的全基因组序列数据进行传统和创新分析 在3,500名60岁或60岁以上的MHAS参与者的子样本中，他们符合LOAD的诊断标准， 健康对照（比例约1：4）;目的2）对WGS优先的基因组发现进行功能验证 3）与科学界分享表型和基因组数据。

Abstract We aim to conduct traditional and innovative genetic analyses of whole-genome sequencing (WGS) data generated from a sub-sample of 3,500 participants from the Mexican Health Aging Study (MHAS). We have already been funded to collect saliva for DNA extraction and to perform genome-wide a association study in this Mexican sample (grant # R56-AG059756, PI: Tosto, Barral, Mayeux). Accumulating evidence supports a strong genetic component underpinning physiopathology of Late onset Alzheimer’s disease (LOAD). European population studies still dominate the pool of available genomic data resulting in a lack of generalizability of findings across diverse and minority populations. By 2020, the prevalence of dementia in Latin America will increase by 120%, compared to 49% in North America. It is therefore pivotal to increase representation of Hispanics and Latinos in genetic investigations. Mexicans are not currently represented in large genetic studies for LOAD. They show a unique genetic profile with one of the highest Native- American ancestral component percentages (~50%). This population may harbor unique LOAD risk/protective alleles, which are rare or absent in other populations. Furthermore, it may shed lights on the contribution of native ancestry on LOAD risk, which is still unknown. Our group has so far collected 9,162 saliva and blood samples from MHAS participants aged 60 and older and stored them at National Cell Repository for Alzheimer’s Disease (NCRAD). MHAS also provides a rich set of phenotypes (demographical, cognitive and medical assessment) with 20-years period of follow-up. The participants that will undergo whole genome sequencing (N~3,500 who meet clinical criteria for dementia and cognitively healthy; ratio 1:4) are characterized by an additional in-depth cognitive evaluation for which we have been already funded. The availability of extensive cognitive endophenotypes will facilitate a plethora of investigations beyond the classical case-control design (i.e. survival analyses and cognitive trajectories); it will ensure the accuracy of LOAD diagnosis, and will facilitate phenotype harmonization across different sequencing cohorts. We propose to: Aim 1) conduct traditional and innovative analysis of the whole genome sequence data generated in a sub-sample of 3,500 MHAS participants 60 years of age or older who meet diagnostic criteria for LOAD and healthy controls (ratio ~1:4); Aim 2) Conduct functional validation of genomic findings prioritized by WGS analyses; Aim 3) Share phenotypic and genomic data with the scientific community.