Evidence for GRN connecting multiple neurodegenerative diseases.

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, GRN, 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 GRN 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 GRN expression in the frontal cortex. GRN expression mediates neuroinflammation function related to multiple neurodegenerative diseases. This analysis suggests shared mechanisms for Parkinson's, Alzheimer's and amyotrophic lateral sclerosis. Published by Oxford University Press on behalf of the Guarantors of Brain 2021. This work is written by US Government employees and is in the public domain in the US.