GXI Interactions

项目总结/摘要 到2050年，全世界将有超过20亿人年龄超过65岁，老年人的人数超过65岁。 在有记载的历史上第一次。这一预测的重大人口变化凸显了 来提高我们对健康大脑老化因素的理解。目前，生物基地 大脑衰老的机制还知之甚少大脑老化（通常集中在认知能力下降）的特点是： 许多表型，无疑涉及多种环境和遗传因素。公然 病理性脑老化见于主要的神经系统疾病，如阿尔茨海默氏病和相关疾病。 痴呆症（ADRD）; ADRD的患病率预计每20年翻一番。在现有的 公共卫生危机，我们现在正在经历一场全球流行病， 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， 短期后果并发症包括急性神经病变、脑病、嗅觉丧失和 缺氧/缺血性脑损伤，以及包括认知障碍和 神经精神紊乱 对SARS-CoV-2的神经生物学反应的个体间差异显著。如同大多数 复杂的表型，因果决定因素可能包括遗传和环境因素。但没有 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，在本发明中， 描述对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健康的大脑老化提供策略， 未来的传染病挑战。我们的项目将评估ADRD相关的遗传基础， 在一个集合中，对SARS-CoV-2感染的内表型反应（在两年期间进行三次检查） 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]、非洲裔美国人[n=125]和 非洲人[n=300]），采用病例/对照设计中的全基因组序列（WGS）数据（75%感染后 25%从未感染对照组）。所产生的数据将有助于估计遗传学在以下方面的重要性： 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数据检测对SARS-CoV-2感染内表型反应的遗传影响 在神经认知测量中检测基因型×感染相互作用（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）寻找基因和基因途径中的序列变异 影响对SARS-CoV-2感染的反应;以及3）测试平均值的群体间变异是否 对感染的反应有遗传因素。这个项目代表了一个大型的， 整合U19应用程序，以检查COVID-19对未充分研究的种族中ADRD风险的影响。 通过这个项目，我们将确定ADRD中差异反应的遗传因素 COVID-19的风险。

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.