Harmonized Diagnostic Assessment of Dementia (DAD) for Longitudinal Aging Study of India (LASI)-Genomic study

总结 遗传因素在阿尔茨海默病（AD）中起着重要作用，有证据表明， 随着年龄的增长，基因在认知中的作用可能会越来越大。我们初步分析了整个 来自LASI-DAD的基因组序列表明，我们的研究对 南亚的遗传变异此外，我们发现，像大多数非非洲人一样， 亚洲人有大约1-3%的祖先来自古代人类--尼安德特人和丹尼索瓦人。的调查 欧亚人已经表明，这段历史在塑造基因和 现代人类的表型变异例如，欧亚人的古老祖先影响了 许多特征，从皮肤色素沉着到高海拔适应， SARS-CoV-2.然而，大多数研究都集中在欧洲人和东亚人身上， 世界其他地方的基因组。此外，还没有研究调查过古体的作用。 祖先在影响阿尔茨海默病或认知表型的风险。 为了填补这一空白，我们的目标是调查古代人类（尼安德特人和丹尼索瓦人） 祖先影响现代人患阿尔茨海默病的风险和认知表型 使用我们LASI-DAD研究的2,700个样本的大数据集。LASI-DAD数据集 包含来自印度不同种族语言群体的2，700名个体，具有广泛的表型 阿尔茨海默病风险和认知表型的信息。详细的基因型和 来自LASI-DAD数据集的表型信息提供了研究 尼安德特人、丹尼索瓦人和来自其他未知人类的基因渗入片段对 现代个体的健康状况，并发现与阿尔茨海默氏症相关的基因渗入 疾病风险。此外，我们现正从其他地区收集更多样本， 研究是一个非常及时的项目，因为我们可以从特定群体中收集更多样本， 用于基因型-表型分析的能力，显示出有希望的结果。 在这个应用中，我们提出了以下具体目标：（1）生成一个地图archai （2）进行关联分析，研究基因组与人类基因组之间的关联。 阿尔茨海默病风险和古代祖先;（3）从其他地区招募样本， 最大限度地发挥其潜力，为未来的人口基因组学研究。

Summary Genetic factors play an important role in Alzheimer’s disease (AD), and there is evidence that genes may play a bigger role in cognition as we age. Our preliminary analysis of the whole genome sequences from LASI-DAD shows that our study has the most comprehensive survey of genetic variation in South Asia. Further, we have uncovered that like most non-Africans, South Asians have ~1-3% ancestry from archaic hominins––Neanderthals and Denisovans. Surveys of Eurasians have shown that this history has played a critical role in shaping the genetic and phenotypic variation in modern humans. For instance, archaic ancestry in Eurasians has impacted numerous traits ranging from skin pigmentation to high altitude adaptation, and response to SARS-CoV-2. However, most studies have focused on Europeans and East Asians, with very few genomes from other parts of the world. Further, no study has investigated the role of archaic ancestry in impacting the risk of Alzheimer’s disease or cognitive phenotypes. To fill this gap, we aim to investigate how archaic hominins (Neanderthal and Denisovan) ancestry impacts the risk of Alzheimer’s disease and cognitive phenotypes in modern humans using the large dataset of 2,700 samples from our LASI-DAD study. The LASI-DAD dataset contains 2,700 individuals from diverse ethnolinguistic groups in India, with extensive phenotype information for Alzheimer’s disease risk and cognitive phenotypes. The detailed genotype and phenotype information from the LASI-DAD dataset provides a unique opportunity to study the impact of Neanderthal, Denisovan and introgressed segments from other unknown hominins on the health of present-day individuals and uncover introgressed genes associated with Alzheimer's disease risk. Moreover, we are currently collecting more samples from additional regions and the study is a very timely project as we can collect more samples from specific groups to increase our power for genotype-phenotype analysis that show promising results. In this application, we propose the following specific aims: (1) to generate a map of archai introgression in modern humans; (2) to perform association analysis to study the association of Alzheimer’s disease risk and archaic ancestry; (3) to recruit samples from additional regions to maximize its potential for future population genomics study.