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Evidence for GRN as part of a neuroinflammatory mechanism connecting common neurodegenerative diseases.

By Mike A Nalls, Cornelis Blauwendraat, Lana Sargent, Dan Vitale, Hampton Leonard, Hirotaka Iwaki, Yeajin Song, Sara Bandres Ciga, Kevin Menden, Faraz Faghri, Peter Heutink, Mark R. Cookson, Andrew Singleton

Posted 07 Dec 2020
medRxiv DOI: 10.1101/2020.12.04.20243600

Background Previous research using genome wide association studies (GWAS) 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. Methods We utilized GWAS, expression quantitative trait locus (eQTL) 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. Findings eQTL analyses combined with GWAS 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. Interpretation GRN expression mediates neuroinflammation function related to general neurodegeneration. This analysis suggests shared mechanisms for Parkinson's, Alzheimer's and amyotrophic lateral sclerosis. Funding National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J. Fox Foundation.

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