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

摘要 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 可能会随着我们年龄的增长在认知方面发挥更大的作用。比较相同和相同的性状之间的相关性的研究 异卵双胞胎表明，情景记忆中30%-60%的差异与 个人，其余的归因于家庭成员没有分享的环境影响。然而， 我们仍然对基因和生活方式之间在发病、进展和发展过程中的复杂相互作用知之甚少。 认知老化，呼吁进一步开展遗传流行病学研究以对抗阿尔茨海默病。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。使用 4.印度人口超过13.5亿，是世界第二大国，人口超过410万 估计患有痴呆症。然而，印度人/南亚人很少在基因组中出现 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2400人进行排序，以更好地定义 印度纵向老龄化研究(LASI)中痴呆风险的突变谱。拉西是一个 对45岁或以上的印度人口进行的全国性和国家级代表性调查 (n=61000)。LASI-DAD痴呆症协调诊断评估是对LASI-DAD的深入研究 晚年认知与痴呆症，抽取了3,000名60岁或以上的LASI受访者作为子样本 管理旨在很好地协调的协调认知评估议定书(HCAP) 世界各地正在进行的关于老龄化的纵向研究，包括健康和退休研究(HRS) 在美国，以及之前在印度的研究。这套丰富的认知表型和脑成像 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 独特的机会，以确定突变谱潜在的痴呆和阿尔茨海默病的风险 印度的样本。 在本申请中，我们提出了以下具体目标：(1)进行全基因组测序 LASI对来自印度12个地区的2400名参与者进行了WGS和群体遗传学分析- DAD；(2)评估已知AD与痴呆基因/遗传变异和认知功能的关系 在测序的LASI-DAD参与者中发挥作用；以及(3)传播WGS数据作为参考小组 东南亚突变和开发、试验和评估东南亚基因分型芯片以确保 对东南亚突变进行适当的分析。

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.