Next Generation Rare Variant Discovery in Multiplex AD Families

世界卫生组织（世卫组织）目前报告了4，793，076例确诊病例， 全球COVID-19感染，316，341人死亡。每一次新的大流行， 在疫苗和药物开发出来之前，整个种群的隔离出现了 作为唯一的替代方案，直到有足够的时间进行疫苗开发。所以一间 一个重要公共卫生目标是确定哪些人必须就地安置，哪些人可以恢复 正常活动.老年人似乎不成比例地受到 病毒虽然免疫功能随着年龄的增长而减弱，但遗传和生活方式因素似乎 大大改变了敏感性。该项目的目标是确定个人谁可能是更多或 由于他们一生都在喝酒，他们的弹性就更小了。酒精使用障碍（AUD）患者可能 接触SARS-CoV-2产生不良后果的风险更大，但低剂量 食用可改善免疫功能。更好地了解酒精使用是否 低剂量与高剂量的不同影响对公共卫生运动至关重要， 公众安全使用酒精。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（HLA）与许多疾病密切相关， 用于个性化抗原特异性疾病预防。有了这些信息，作为 未来的常规医疗检查，将使我们能够将人口分为 需要庇护的人和不需要的人该项目将确定 使用HLA基因变异沿着筛选酒精使用作为分层的重要部分 在病毒性流行病爆发时的人口数量。 目前的建议建立在参与者的现有资源基础上， 完成测序和/或HLA血清学并利用广泛的酒精使用史， 精神病诊断和基线时获得的健康史。新的访谈内容涉及 酒精使用，远端和近端，当前健康状况，以及SARS暴露史- CoV-2病毒将使我们能够确定它们对感染和进展的贡献。我们将 将患有AUD的人与没有AUD的人以及高风险与低风险的未受影响的成员进行对比 家庭（目标1）。在目标2中，我们将评估最近和过去的酒精消费水平， 反应将检测主要组织相容性复合体（HLA）区域的遗传变异， 与已证实暴露者的结局相关（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).