Next Generation Rare Variant Discovery in Multiplex AD Families

世界卫生组织(世卫组织)目前报告4,793,076例确诊病例。 新冠肺炎感染在全球范围内导致316,341人死亡。随着每一次新的大流行，人口处于 风险，直到疫苗和药物可以被开发出来。出现了对整个人口的隔离 在疫苗研发的足够时间过去之前，作为唯一的选择。因此，一个 重要的公共卫生目标是确定谁必须在适当的地方避难，谁可以恢复 正常活动。老年人似乎不成比例地受到 病毒。尽管免疫功能随年龄增长而减弱，但遗传和生活方式因素似乎 极大地改变了敏感度。该项目的目标是确定可能更多或更多 由于终生饮酒，他们的适应能力较差。有酒精使用障碍(AUD)的人可能 暴露于SARS-CoV-2的不良后果的风险较大，但剂量较低 消费可能会改善免疫功能。更好地理解饮酒是否会对 低剂量与高剂量的不同效果对公共卫生活动至关重要，这些活动建议 向公众宣传安全饮酒。主要组织相容性基因座(MHC)的遗传变异 位于6号染色体上，在免疫功能中起着重要作用。人类的变异 白细胞抗原(HLAs)与多种疾病密切相关，有希望 用于个性化的抗原特异性疾病预防。将此信息作为以下内容的一部分 未来的常规体检，将使我们能够将人口分成 需要避难所的人和那些不需要的人。这一项目将决定 利用人类白细胞抗原基因变异和酒精使用筛查作为分层的重要组成部分 在病毒流行开始时的人群。 本提案建立在与会者现有资源基础上，对这些参与者来说 测序和/或人类白细胞抗原血清学已经完成并利用了大量的酒精使用史， 精神诊断，以及基线时获得的健康史。关于以下问题的新采访 酒精使用，包括远端和近端，目前的健康状况，以及SARS的接触史- CoV-2病毒将使我们能够确定它们对感染和进展的贡献。我们会 将患有AUD的人与那些没有和未受影响的高风险成员与低风险成员进行比较 (目标1)中的族。在目标2中，我们将评估最近和过去的酒精消费水平对病毒的影响 回应。将对主要组织相容性复合体(HLA)区域的遗传变异进行测试 与那些被证明已经暴露的人的结果相关(目标3)。

The World Health Organization (WHO) is currently reporting 4,793,076 confirmed cases of COVID-19 infection world-wide with 316,341 deaths. With each new pandemic the population is at risk until vaccines and medications can be developed. Quarantine of the entire population appears to be only alternative until sufficient time elapses for vaccine development. Therefore, an important public health goal is to determine who must be sheltered in place and who can resume normal activities. Older individuals appear to be disproportionately adversely affected by the virus. Although immune functioning tends to wane with age, genetic and lifestyle factors appear to greatly alter susceptibility. The goal of this project is to identify individuals who may be more or less resilient due to their lifetime use of alcohol. Those with an alcohol use disorder (AUD) may have a greater risk for adverse consequences of SARS-CoV-2 exposure, yet low dose consumption may improve immune functioning. A better understanding of whether alcohol use has a different effect at low doses than at high doses is critical to public health campaigns that advise the public on safe use of alcohol. Genetic variation in the Major Histocompatiblity Locus (MHC) located on chromosome 6 plays an important role in immune functioning. Variation in the human leucocyte antigens (HLA) have been significantly associated with many diseases and hold promise for personalized antigen-specific disease prevention. Having this information available, as part of routine medical screening in the future, would enable us to stratify the population into those needing sheltering in place and those who do not. This project would determine the feasibility of using HLA gene variation along with screening for alcohol use as an important part of stratifying the population at the onset of viral epidemics. The present proposal builds on existing resources from participants for whom exome sequencing and/or HLA serology was completed and utilizes the extensive alcohol use histories, psychiatric diagnoses, and health histories obtained at baseline. New interviews concerning alcohol use, both distal and proximal, current health status, and exposure histories for the SARS- CoV-2 virus will enable us to determine their contribution to infection and progression. We will contrast those with AUD with those without and unaffected members of high risk versus low risk families in (Aim 1). In Aim 2, we will assess levels of recent and past alcohol consumption to viral response. Genetic variation in the major histocompatibility complex (HLA) region will be tested for association with outcome among those that are demonstrated to have been exposed (Aim 3).