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; 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.

项目摘要/摘要 到2050年，全球超过20亿人口将超过65岁，老年人人数超过了 记录历史上第一次孩子。这预测的主要人口转变强调了重要性 提高我们对有助于健康大脑衰老的因素的理解。目前，生物基础 大脑衰老的了解很少。大脑衰老（通常以认知能力下降为特征）的特征是 无疑涉及多种环境和遗传因素的许多表型。公开 病理大脑衰老在主要神经系统疾病（例如阿尔茨海默氏病）和相关性疾病中可见 痴呆症（ADRD）; ADRD的患病率预计每20年将翻一番。最重要的是 公共卫生危机，我们现在正在经历一个全球大流行，似乎对 神经功能。越来越多的证据表明SARS-COV-2感染会引起神经系统 短期后果的并发症，包括急性神经病，脑病，厌食和 低氧/缺血性脑损伤，以及长期后果，包括认知障碍和 神经精神灾难。 标志着神经生物学反应的个体差异。与大多数一样 复杂的表型，因果决定剂可能包括遗传和环境因素。但是，不 遗传流行病学研究尚未考虑对感染的差异神经表型反应。那， 描述与ADRD相关的神经形型对SARS-COV-2的遗传结构将提供 重要的生物学见解，反过来可以为促进健康的大脑衰老的策略提供 存在未来的传染性挑战。我们的项目将评估与ADRD相关的遗传基础 内生植物型反应（将三年的三年检查与SARS-COV-2感染交换了两年） 来自潜水员种群的年龄较大（> 60岁）的成年人（来自阿根廷的美国印第安人[n = 3000]，美国本地人 美国人[n = 250]，墨西哥美国人[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/控制设计中使用整个基因组序列（WGS）数据（感染后75％ 病例，25％从未感染对照）。生成的数据将估算遗传学在 疾病反应和对反应涉及的关键基因的鉴定。我们的具体目的是：1） 使用WGS数据检测对SARS-COV-2感染内生植物型反应的遗传影响 在神经认知测量中测试基因型×感染相互作用（神经认知测量，神经影像学 措施和基于血液的生物标志物）； 2）搜索基因和基因途径的序列变化 影响对SARS-COV-2感染的反应； 3）测试平均人群之间的变化 对感染的反应具有遗传成分。该项目代表了大型， 综合的U19应用程序以检查Covid-19对ADRD在知识种族中的风险的影响。 通过拟议的项目，我们将确定ADRD中基本差异反应的因果遗传因素 COVID-19的风险。