Next Generation Rare Variant Discovery in Multiplex AD Families

The World Health Organization (WHO) is currently reporting 4,793,076 confirmed cases ofCOVID-19 infection world-wide with 316,341 deaths. With each new pandemic the population is atrisk until vaccines and medications can be developed. Quarantine of the entire population appearsto be only alternative until sufficient time elapses for vaccine development. Therefore, animportant public health goal is to determine who must be sheltered in place and who can resumenormal activities. Older individuals appear to be disproportionately adversely affected by thevirus. Although immune functioning tends to wane with age, genetic and lifestyle factors appear togreatly alter susceptibility. The goal of this project is to identify individuals who may be more orless resilient due to their lifetime use of alcohol. Those with an alcohol use disorder (AUD) mayhave a greater risk for adverse consequences of SARS-CoV-2 exposure, yet low doseconsumption may improve immune functioning. A better understanding of whether alcohol use hasa different effect at low doses than at high doses is critical to public health campaigns that advisethe 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 humanleucocyte antigens (HLA) have been significantly associated with many diseases and hold promisefor personalized antigen-specific disease prevention. Having this information available, as part ofroutine medical screening in the future, would enable us to stratify the population into thoseneeding sheltering in place and those who do not. This project would determine the feasibility ofusing HLA gene variation along with screening for alcohol use as an important part of stratifyingthe population at the onset of viral epidemics. The present proposal builds on existing resources from participants for whom exomesequencing and/or HLA serology was completed and utilizes the extensive alcohol use histories,psychiatric diagnoses, and health histories obtained at baseline. New interviews concerningalcohol 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 willcontrast those with AUD with those without and unaffected members of high risk versus low riskfamilies in (Aim 1). In Aim 2, we will assess levels of recent and past alcohol consumption to viralresponse. Genetic variation in the major histocompatibility complex (HLA) region will be tested forassociation with outcome among those that are demonstrated to have been exposed (Aim 3).