Genetic and real-world clinical data, combined with empirical validation, nominate JAK-STAT signalling as a target for Alzheimer's Disease therapeutic development

Abstract

As Genome Wide Association Studies (GWAS) have grown in size, the number of genetic variants that have been nominated for an increasing number of diseases has correspondingly increased. Despite this increase in the number of associated SNPs per disease, their biological interpretation has in many cases remained elusive. To address this, we have combined GWAS results with an orthogonal source of evidence, namely real-world, routinely collected clinical data from more than 6 million patients in order to drive target nomination. First we show that when examined at a pathway level, analysis of all GWAS studies groups Alzheimer's disease (AD) in a cluster with disorders of immunity and inflammation. Using clinical data we show that the degree of comorbidity of these diseases with AD correlates with the strength of their genetic association with molecular participants in the JAK-STAT pathway. Using four independent open-science datasets we then find evidence for altered regulation of JAK-STAT pathway genes in AD. Finally, we use both in vitro and in vivo rodent models to demonstrate that A-beta induces gene expression of key drivers of this pathway, providing experimental evidence validating these data-driven observations. These results therefore nominate JAK-STAT anomalies as a prominent aetiopathological event in AD and hence potential target for therapeutic development, and moreover demonstrate a de-novo multi-modal approach to derive information from rapidly increasing genomic datasets.