GXI Interactions

GXI 交互

• 批准号: 10628511
• 负责人: John Blangero
• 金额: $ 60.95万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628511
• 关键词: 2019-nCoV; Acute; Acute Respiratory Distress Syndrome; Adult; African; African American population; Age; Age Years; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amerindian; Anosmia; Argentina; Biological; COVID-19; COVID-19 impact; COVID-19 morbidity; COVID-19 mortality; COVID-19 patient; Caucasians; Cause of Death; Child; China; Cities; Complex; Data; Dementia; Disease; Elderly; Encephalopathies; Environmental Risk Factor; Ethnic Origin; Etiology; Fostering; Future; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Variation; Genotype; Heritability; Hypoxic-Ischemic Brain Injury; Impaired cognition; Individual; Infection; Joints; Measures; Methods; Mexican Americans; Modeling; Morbidity - disease rate; Native Americans; Nerve Degeneration; Nervous System Physiology; Neurobiology; Neurocognitive; Neurologic; Neurons; Neuropathy; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Patients; Persons; Phenotype; Pneumonia; Population; Population Heterogeneity; Predisposition; Prevalence; Proteins; Public Health; Puerto Rican; Recording of previous events; Risk; SARS-CoV-2 infection; South American; Stroke; Symptoms; Testing; Time; Variant; acute hypoxemic respiratory failure; aging brain; blood-based biomarker; brain based; cohort; dementia risk; design; endophenotype; experience; genetic architecture; genetic epidemiology; genome-wide; health care service utilization; high risk; human old age (65+); identity by descent; improved; insight; inter-individual variation; mortality; nervous system disorder; neuroimaging; neuropsychiatry; pandemic disease; response; whole genome

PROJECT SUMMARY/ABSTRACT By 2050, more than 2 billion people worldwide will be over the age of 65, with older adults outnumbering children for the first time in recorded history. This predicted major demographic shift highlights the importance of improving our understanding of factors that contribute to healthy brain aging. Currently, the biological bases of brain aging are poorly understood. Brain aging (often focused on cognitive decline) is characterized by numerous phenotypes that undoubtedly involve multiple environmental and genetic factors. Overtly pathological brain aging is seen in major neurological diseases such as Alzheimer’s disease and related dementias (ADRD); the prevalence of ADRD is expected to double every 20 years. On top of this existing public health crisis, we are now experiencing a global pandemic that appears to negatively influence neurological function. Growing evidence indicates that SARS-CoV-2 infection causes neurological complications of short-term consequence including acute neuropathy, encephalopathy, anosmia, and hypoxic/ischemic brain injury, and longer-term consequences including cognitive impairment and neuropsychiatric disturbances. The interindividual variation in the neurobiological responses to SARS-CoV-2 is marked. As with most complex phenotypes, causal determinants likely include both genetic and environmental factors. However, no genetic epidemiological study has yet considered differential neurophenotypic response to infection. Thus, delineating the genetic architecture of ADRD-relevant neurophenotypic responses to SARS-CoV-2 will offer important biological insights, which in turn could provide strategies for fostering healthy brain aging in the presence of future infectious challenges. Our project will assess the genetic basis of ADRD-relevant endophenotypic response (across a two year period with three examinations) to SARS-CoV-2 infection in a set of older (>60 years of age) adults from diverse populations (Amerindians from Argentina [ n=3000], US Native Americans [n=250], Mexican Americans [n=500], Puerto Ricans [n=125], African Americans [n=125], and Africans [n=300]) using whole genome sequence (WGS) data in a case/control design (75% post-infection cases, 25% never infected controls). The data generated will enable estimating the importance of genetics in disease response and the identification of key genes involved in the response. Our specific aims are to: 1) detect genetic influences on endophenotypic responses to SARS-CoV-2 infection using WGS data through testing for genotype×infection interaction in neurocognitive measures (neurocognitive measures, neuroimaging measures, and blood-based biomarkers); 2) search for sequence variation in genes and gene pathways influencing response to SARS-CoV-2 infection; and 3) test whether between-population variation in mean responses to infection has a genetic component. This project represents the genetic component of a large, integrated U19 application to examine the effect of COVID-19 on risk for ADRD in understudied ethnicities. Through the proposed project, we will identify causal genetic factors that underly differential response in ADRD risk to COVID-19.

项目概要/摘要 到 2050 年，全球将有超过 20 亿人年龄在 65 岁以上，其中老年人数量将超过 有记录的历史上第一次出现了儿童。这一预测的重大人口变化凸显了重要性 提高我们对促进大脑健康老化的因素的理解。目前，生物基地 人们对大脑衰老的影响知之甚少。大脑老化（通常集中于认知能力下降）的特点是 众多的表型无疑涉及多种环境和遗传因素。公然地 病理性脑老化见于主要神经系统疾病，如阿尔茨海默病和相关疾病 痴呆症（ADRD）； ADRD 的患病率预计每 20 年就会翻一番。在这个现有的基础上 公共卫生危机，我们现在正在经历一场全球大流行，这似乎对我们产生了负面影响 神经功能。越来越多的证据表明 SARS-CoV-2 感染会导致神经系统疾病 短期后果的并发症包括急性神经病、脑病、嗅觉丧失和 缺氧/缺血性脑损伤，以及长期后果，包括认知障碍和 神经精神障碍。 对 SARS-CoV-2 的神经生物学反应存在明显的个体差异。与大多数人一样 复杂的表型，因果决定因素可能包括遗传和环境因素。然而，没有 遗传流行病学研究尚未考虑对感染的不同神经表型反应。因此， 描绘对 SARS-CoV-2 的 ADRD 相关神经表型反应的遗传结构将提供 重要的生物学见解，这反过来又可以为促进大脑健康老化提供策略 未来传染性挑战的存在。我们的项目将评估 ADRD 相关的遗传基础 一组中对 SARS-CoV-2 感染的内表型反应（历时两年，进行三次检查） 来自不同人群的老年人（>60 岁）（来自阿根廷的美洲印第安人 [ n=3000]、美国原住民 美国人 [n=250]、墨西哥裔美国人 [n=500]、波多黎各人 [n=125]、非裔美国人 [n=125] 和 非洲人 [n=300]）在病例/对照设计中使用全基因组序列 (WGS) 数据（75% 感染后 病例中，25% 从未感染对照）。生成的数据将能够估计遗传学在 疾病反应和识别参与反应的关键基因。我们的具体目标是：1) 使用 WGS 数据检测遗传对 SARS-CoV-2 感染内表型反应的影响 神经认知测量中基因型×感染相互作用的测试（神经认知测量、神经影像学 测量和基于血液的生物标志物）； 2）寻找基因和基因通路中的序列变异 影响对 SARS-CoV-2 感染的反应； 3）测试群体间平均值是否存在差异 对感染的反应具有遗传成分。该项目代表了一个大型的遗传组成部分， 综合 U19 应用程序，用于检查 COVID-19 对未充分研究的种族的 ADRD 风险的影响。 通过拟议的项目，我们将确定 ADRD 差异反应的致病遗传因素 COVID-19 的风险。