Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD): Epigenomic Assays

摘要 DNA的表观遗传修饰，如DNA甲基化，一直与时间顺序密切相关 年龄，并可用来估计个体的年龄加速。表观遗传因素也可能调节或改变 阿尔茨海默病相关遗传变异的影响。鉴于表观基因组的动态性质和许多影响因素 (环境和遗传)，在多个时间点测量甲基化的纵向研究正在进行中 越来越被认为是分析复杂疾病表观遗传学的最合适方法。然而， 估计表观遗传学变化的纵向研究在世界上任何地方都非常有限，而且几乎 在以总体为基础的代表性样本中不存在。此外，表观遗传学方面的工作也很少。 低收入非西方国家的AD和认知功能。 为了填补这一空白，我们的目标是在协调诊断中测量纵向表观基因组变异 用于印度纵向老龄化研究(LASI-DAD)的DNA样本中的痴呆症评估 已提取(第一波)和目前正在采集的静脉血样(第二波)。这项工作将使Essential 衰老、认知障碍和阿尔茨海默病及其相关表观遗传学预测因子的研究 印度南亚人的痴呆(ADRD)，以及对表观遗传介体和修饰物的研究 认知障碍和痴呆症的遗传风险。此外，由于表观基因组变异经常反映出 与AD相关的风险因素的环境变化(例如，环境污染物， 社会经济和社会压力源、健康行为和饮食习惯)，关键是评估潜力 这些社会、环境和个人风险因素可能影响疾病的生物机制 在南亚和其他非西方人口中，包括他们如何随着时间的变化。 在这一应用中，我们提出了以下具体目标：(1)同时进行表观基因组分析 对于纵向研究，首先从波1 VBS(1a)中提取DNA，对波1和波2进行分类和配对 样品和用于甲基化分析的试板(1b)，并对配对样品进行表观基因组分析 (在两个不同的时间点为同一个人提取的DNA，相隔5年)使用Infinium甲基化 EPIC 2珠片；(2)进行跨实验室校准研究，以便将来进行越野比较， 特别是健康和退休研究(HRS)及其国际研究网络。

Summary Epigenetic modifications of DNA, such as DNA methylation, have been strongly associated with chronological age and can be used to estimate age acceleration in individuals. Epigenetic factors may also mediate or modify the effects of AD-related genetic variants. Given the dynamic nature of epigenome and many influencing factors (both environmental and genetic), longitudinal studies that measure methylation at multiple timepoints are being increasingly recognized as the most suitable approach to analyze the epigenetics of complex diseases. However, longitudinal studies to estimate change in epigenetics are very limited anywhere in the world and are virtually non-existent in population-based representative samples. Furthermore, little work has been done on epigenetics and AD and cognitive function in lower income, non-Western countries. To fill this gap, we aim to measure longitudinal epigenomic variation in the Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD) in DNA samples that are already extracted (Wave 1) and venous blood samples currently being collected (Wave 2). This work will enable essential studies of the epigenetic predictors of aging, cognitive impairment, and Alzheimer’s disease and related dementias (ADRD) in South Asians from India, as well as the study of epigenetic mediators and modifiers of genetic risk for cognitive impairment and dementia. Moreover, since epigenomic variation often reflects environmental variation with risk factors that have been associated with AD (e.g., environmental pollutants, socioeconomic and social stressors, health behaviors, and dietary habits), it is critical to evaluate potential biological mechanisms by which these social, environmental, and individual risk factors may influence disease in South Asian and other non-Western populations, including how they change over time. In this application, we propose the following specific aims: (1) to simultaneously conduct epigenomic assays for longitudinal study by first extracting DNA from the Wave 1 VBS (1a), sorting and pairing wave 1 and wave 2 samples and preparing plates for methylation assays (1b), and conducting epigenomic assays for paired samples (DNAs extracted for the same individuals at two different timepoints, 5-years apart) using the Infinium Methylation EPIC 2 BeadChip; (2) to conduct a cross-laboratory calibration study for future cross-country comparisons, particularly with the Health and Retirement Study (HRS) and its international network of studies.