Analysis of Alzheimer's disease Polygenic Risk Scores using RNA- sequencing provides further novel biological pathways

Polygenic risk scores (PRS) have been widely adopted as a tool for measuring common variant liability and it has been shown to predict lifetime risk of Alzheimers disease (AD) development. However, the relationship between PRS and AD pathogenesis is largely unknown. We aimed to address some of the knowledge gaps with respect to the downstream molecular consequences associated with PRS. We also make a direct comparison of the disrupted biological mechanisms in a case/control classification and in response to PRS in the same individuals. We performed an integrative computational analysis of the transcriptome of the largest human brain-derived cohort sample (288 individuals; cerebellum and temporal cortex; MayoRNAseq; AMP-AD) with matched AD genetic and gene-expression data (WGS; bulk-brain RNA-seq). There was little overlap in terms of differentially expressed genes in case/control and PRS analyses, but a consensus of commonly disrupted biological mechanisms. Genes implicated by previous AD GWAS were found to be significantly enriched with respect to PRS in temporal cortex only. We identified mechanisms that were previously implicated in AD, including immune/stress response, lipid/cholesterol/fatty acid metabolism, endosome, death/apoptosis, neuronal processes, ageing and the involvement of glial cells. We also provide novel evidence for the significant involvement in AD of cellular structures, including the Golgi apparatus and endoplasmic reticulum as well as mitochondrial function. The largely common biological mechanisms between a case/control classification and in association with PRS suggests that PRS stratification can be used for studies where suitable case/control samples are not available or the selection of individuals with high and low PRS in clinical trials.