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，有证据表明基因 随着年龄的增长，大脑在认知中的作用会越来越大。研究比较了同卵双生子和异卵双生子的性状相关性， 异卵双胞胎的研究表明，情景记忆中30- 60%的差异与遗传组成有关。 个人，其余归因于环境的影响，而不是由家庭成员共享。然而，在这方面， 我们仍然对基因和生活方式在发病、进展和 认知老化，呼吁进一步开展遗传流行病学研究以对抗AD。此外，绝大多数 研究认知遗传学的工作已经在欧洲血统的人群中进行。与 印度人口超过13.5亿，是世界上第二大国家，人口超过410万 估计患有痴呆症然而，印度/南亚人群在基因组中很少有代表性， 痴呆症的研究。 为了填补这一空白，我们建议对来自印度12个地区的2，400名个体进行测序，以更好地定义 在印度纵向老龄化研究（LASI）中，突变谱是痴呆风险的基础。LASI是一个 在全国和邦一级，对45岁或以上的印度人口进行代表性调查 （N= 61，000）。LASI痴呆的统一诊断评估（LASI-DAD）是一项深入研究， 晚年认知和痴呆症，吸引了3,000名年龄在60岁或以上的LASI受访者的子样本， 管理协调认知评估协议（HCAP），该协议旨在协调 全球正在进行的老龄化纵向研究，包括健康与退休研究（HRS） 在美国，以及在印度的研究。这套丰富的认知表型沿着脑成像 在这个子样本中收集的各种其他健康和社会环境表型将为我们提供一个 这是一个独特的机会，可以在一个代表性的研究中确定痴呆和AD的潜在风险突变谱。 印度的样本。 在本申请中，我们提出以下具体目标：（1）进行全基因组测序 (WGS)对来自印度12个地区的2,400名参与者进行了LASI调查， DAD;（2）评估已知AD与痴呆基因/遗传变异和认知功能之间的关联。 功能排序LASI-DAD参与者;和（3）传播WGS数据作为参考面板， 东南亚突变和开发，试点，并评估东南亚基因分型芯片，以确保 东南亚突变的正确检测。

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. Studies comparing the correlation in traits between identical and fraternal twins suggest 30-60 percent of the variance in episodic memory is related to the genetic makeup of individuals, with the remainder attributed to environmental influences not shared by family members. However, we still know very little about such complicated interplay between genes and lifestyle in onset, progress, and cognitive aging, calling for furthering genetic epidemiologic research to fight AD. Further, the vast majority of work examining the genetics of cognition has been performed in populations of European ancestry. With greater than 1.35 billion people, India is the second largest country in the world with over 4.1 million people estimated to have dementia. However, Indian/South Asian populations are rarely represented in genomic studies of dementia. To fill this gap, we propose to sequence 2,400 individuals from 12 regions of India to better define the mutational spectrum underlying dementia risk in the Longitudinal Aging Study of India (LASI). LASI is a representative, both nationally and at state-level, survey of the Indian population at age 45 or older (N=61,000). The Harmonized Diagnostic Assessment of Dementia for LASI (LASI-DAD) is an in-depth study of late-life cognition and dementia, drawing a sub-sample of 3,000 LASI respondents aged 60 or older and administering the Harmonized Cognitive Assessment Protocol (HCAP) that was designed to harmonize well with ongoing longitudinal studies of aging around the world, including the Health and Retirement Study (HRS) in the United States, and prior studies in India. This rich set of cognitive phenotypes along with brain imaging and a variety of other health and social environment phenotypes collected in this sub-sample will give us a unique opportunity to identify the mutational spectrum underlying risk of dementia and AD in a representative sample of India. In this application, we propose the following specific aims: (1) to perform whole genome sequencing (WGS) and population genetic analyses of 2,400 participants from 12 regions of India surveyed in the LASI- DAD; (2) to evaluate the association between known AD and dementia gene/genetic variants and cognitive function in sequenced LASI-DAD participants; and (3) to disseminate the WGS data as a reference panel for Southeast Asian mutations and develop, pilot, and evaluate a Southeast Asian genotyping chip to ensure proper assay of Southeast Asian mutations.