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

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).