Evaluating the Classification Accuracy of Expression Quantitative Trait Loci Calculated Polygenic Risk Scores in Alzheimer’s Disease

Abstract

Polygenic risk scores (PRS) hold promise for the early identification of those at risk from neurodegenerative disorders such as Alzheimer’s Disease (AD), allowing for intervention to occur prior to neuronal damage. The current selection of informative single nucleotide polymorphisms (SNPs) to generate the risk scores is based on the modelling of large genome-wide association data using significance thresholds. However, the biological relevance of these SNPs is largely unknown. This study, in contrast, aims to identify SNPs with biological relevance to AD and then assess them for their ability to accurately classify cases and controls. Samples selected from the Brains for Dementia Research (BDR) were used to produce gene expression data to identify potential expression quantitative trait loci (eQTLs) relevant to AD. These SNPs were then incorporated into a PRS model to classify AD and controls in the full BDR cohort. Models derived from these eQTLs demonstrate modest classification potential with an accuracy between 61% and 67%. Although the model accuracy is not as high as some values in the literature based on significance thresholds from genome-wide association studies, these models may reflect a more biologically relevant model, which may provide novel targets for therapeutic intervention.