Do Genetic Risk Variants for Alzheimer's Disease have a Pleotropic Effect on Sleep? - ABSTRACT There is a bidirectional relationship between sleep disturbances and Alzheimer's disease (AD). Cohort studies show that there are short sleep durations in individuals who are cognitively intact who go on to develop dementia. It has been argued that short sleep duration may be an early manifestation of disease. There is, however, an alternative explanation; there could be an effect on sleep duration due to genetic variants that confer risk for AD also having an effect on sleep (a pleotropic effect of these gene variants). The goal of this study is to assess this possibility. AD, sleep duration, and other aspects of sleep are the result of polygenetic variations coupled with environmental influences. The nature of the genetic variants conferring risk for AD as well as sleep duration and other aspects of sleep have been determined by genome-wide association studies (GWAS). While it is commonly assumed that the causative gene is the nearest gene to the locus identified by association, this is not a valid assumption. Our group has developed an approach based on determining chromatin interactions to identify putative causative genes. This is called variant-to-gene mapping. Since chromatin interactions vary in different cell types, we generated data for multiple relevant cell types. We have done this analysis for results of GWAS for AD and present these results in our proposal. We plan to build on this in two ways to address our global hypothesis of pleiotropy. First, we will conduct variant-to-gene mapping for AD, sleep duration and other relevant sleep phenotypes to look for colocalization, i.e., to determine if there is evidence for identified causative genes conferring risk for AD that also affect sleep duration and/or other sleep phenotypes. This aim is in silico and involves a bioinformatic approach. This will be complimented by studies in zebrafish. We will use CRISPR to create loss of function in zebrafish of genes that are found in the analysis of chromatin interactions in neurons and are likely to be causative genes for risk of AD. These fish will have high-throughput assessment of sleep amounts, microarchitecture of sleep (bout lengths and numbers), and arousal threshold as a measure of sleep depth. Thus, we will seek direct evidence that putative causative genes for risk of AD have an effect on sleep. These complimentary approaches will definitely address our global hypothesis.
