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• W2980471540 abstract "To date, the APOEɛ4 allele is the best known genetic risk factor of AD, while the APOEɛ2 allele is known to protect against AD. However, some APOEɛ4 allele carriers remain AD-free, and some APOEɛ2 carriers have signs and symptoms of dementia. In order to explain this disparity in genotye-phenotype relationship, we developed a method that focuses on these paradoxical responders and measures the degree of mutational selection on each individual gene as a ratio between mutational burden (scored by a fundamental equation of evolution, called the Evolutionary Action (EA) equation) and background mutation rate. This allows us to quantify the deviation in mutational EA burden of a gene against those with similar background mutation rate. For each gene, we then compare the deviations in the two populations of interest (APOEɛ2 AD carriers and APOEɛ4 healthy individuals) to identify outliers with apparent potential for protective or pathogenic qualities. We then tested the involvement of these genes in Drosophila models of AD-associated pathophysiology. We found ∼200 protective or pathogenic genes using a z-score threshold of 2.5 (>99thpercentile). As a computational validation, we saw that the protective genes are depleted of high-impact variants in APOEɛ4 AD patients compared to healthy APOEɛ4 carriers, while pathogenic genes have an overabundance of high-impact variants in APOEɛ2 AD carriers compared to APOEɛ2 healthy individuals. Moreover, the gene set is highly enriched for dysregulated expression in the brains of AD patients. Strikingly, 46.3% of the fly homologs tested modified motor performance deficits induced by Tau or APP, both of which are responsible for pathological hallmarks of AD. Furthermore, many of these genes harbor variants with odds ratio greater than 2 in the human AD population. We conclude that this method successfully identifies protective or pathogenic modifiers of APOE in AD and allow for a tractable analysis of specific variants by quantitatively distinguishing genes under differential selection pressures. Identification of such genes and how they interact together would allow better understanding of epistatic relationships in Alzheimer's disease and provide additional insight into novel drug targets for therapeutic exploration." @default.
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• W2980471540 date "2019-07-01" @default.
• W2980471540 modified "2023-09-28" @default.
• W2980471540 title "P4-493: IDENTIFYING GENETIC MODIFIERS OF APOE VIA IMPUTATION OF DEVIATION IN EVOLUTIONARY ACTION LOAD IN ALZHEIMER'S DISEASE" @default.
• W2980471540 doi "https://doi.org/10.1016/j.jalz.2019.08.039" @default.
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