Loss of the Y chromosome in Alzheimer?s Disease

 
   Lead Investigator:    Renee Laux
   Institution      :    Case Western
   E-Mail           :    audrey.lynn@case.edu
   Proposal ID      :    1006



   Proposal Description:
   The majority of genetic studies of complex disease (including studies of Alzheimer?s) have exclusively explored via germline inherited variation on the autosomes for the discovery of new risk alleles. However, recent has increasingly been able to show that during life acquired mutations, such as mosaic loss of chromosome Y (LOY) in peripheral blood, are associated with increased risk for various human conditions including cancer and AD (Forsberg et al., 2017). While some studies are underway (including those in the) to explore the role of X chromosome variation in AD risk, the Y chromosome is generally                                               uncharacterized, and has long been considered a genetic wasteland (de Carvalho and Santos, 2005 Hughes and Rozen, 2012). However, very early cytogenetic studies illustrated the mosaic loss of chromosome Y among aging men (JACOBS et al., 1963 Pierre and Hoagland, 1972) (22 and 23), though the functional and/or ramifications of this genetic aberration has remained unclear. Here, LOY is discussed as a mosaic event with a mixture of cells with and without the Y chromosome in the peripheral blood of aging men. At the cellular level, LOY is a binary state, either a blood cell has a Y                                                chromosome or not. On the level of an individual, on the other hand, LOY is a continuous estimate ranging from zero to 100 of blood cells affected, with all or none of the blood cells carrying a Y chromosome, respectively. LOY in blood is more common in elderly men and in a recently published data set it was found that 7, 14, 18 and 20 of men was affected in the ages of lt=65, 66-75, 76-85 and gt=86, respectively (Dumanski et al., 2016). LOY was originally thought to be a neutral and natural part of male aging (occurring in 15 of males gt 70 years of age), but recent studies have illustrated that         LOY is a risk factor for both all-cause and non-hematological cancer mortality (Forsberg et al., 20