Evidence for <i>GRN</i> connecting multiple neurodegenerative diseases

Abstract

Previous research using genome-wide association studies has identified variants that may contribute to lifetime risk of multiple neurodegenerative diseases. However, whether there are common mechanisms that link neurodegenerative diseases is uncertain. Here, we focus on one gene, <i>GRN</i>, encoding progranulin, and the potential mechanistic interplay between genetic risk, gene expression in the brain and inflammation across multiple common neurodegenerative diseases. We utilized genome-wide association studies, expression quantitative trait locus mapping and Bayesian colocalization analyses to evaluate potential causal and mechanistic inferences. We integrate various molecular data types from public resources to infer disease connectivity and shared mechanisms using a data-driven process. Expression quantitative trait locus analyses combined with genome-wide association studies identified significant functional associations between increasing genetic risk in the <i>GRN</i> region and decreased expression of the gene in Parkinson's, Alzheimer's and amyotrophic lateral sclerosis. Additionally, colocalization analyses show a connection between blood-based inflammatory biomarkers relating to platelets and <i>GRN</i> expression in the frontal cortex. <i>GRN</i> expression mediates neuroinflammation function related to multiple neurodegenerative diseases. This analysis suggests shared mechanisms for Parkinson's, Alzheimer's and amyotrophic lateral sclerosis.