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3500名参与者的子样本生成。我们有 已经被资助收集唾液用于DNA提取并在全基因组范围内进行关联研究 墨西哥样本(赠款#R56-AG059756，PI：Tosto，Barral，Mayeux)。 越来越多的证据支持迟发性生理病理学的强大遗传成分 阿尔茨海默病(LOAD)。欧洲人口研究仍在现有基因组数据库中占据主导地位 这导致研究结果在不同群体和少数群体中缺乏普遍性。到2020年，普及率 拉丁美洲的痴呆症发病率将增加120%，而北美的这一比例为49%。因此，它对 增加拉美裔和拉丁裔在基因研究中的代表性。墨西哥人目前不是 在对LOAD的大型遗传研究中具有代表性。他们表现出独特的基因特征，是世界上最高的原住民之一- 美国人的祖先构成百分比(~50%)。这一人群可能存在独特的负荷风险/防护 等位基因，这在其他种群中是罕见的或没有的。此外，它可能会揭示原住民的贡献 祖先对负载的风险，这还是个未知数。 到目前为止，我们小组已经从60岁及以上的MHAS参与者那里收集了9162份唾液和血液样本 将它们储存在阿尔茨海默病国家细胞库(NCRAD)。MHAS还提供了一组丰富的 表型(人口学、认知学和医学评估)，随访20年。这个 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和 认知健康；比例为1：4)的特征是额外的深入认知评估，我们对此 已经得到了资助。广泛的认知内表型的可获得性将促进过多的 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 确保负荷诊断的准确性，并将促进不同测序的表型协调 一群人。 我们建议：目标1)对产生的全基因组序列数据进行传统的和创新的分析 在3500名60岁或以上的MHAS参与者中，他们符合负荷和 健康对照(比例约1：4)；目标2)对WGS优先考虑的基因组发现进行功能验证 分析；目的3)与科学界共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.