Title : GRN Mutations Are Associated with Lewy Body Dementia
Language : English
Author, co-author : Reho, Paolo [> >]
Koga, Shunsuke [> >]
Shah, Zalak [> >]
Chia, Ruth [> >]
Krüger, Rejko [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience]
May, Patrick [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core]
Consortium, The International L. B. D. Genomics [> >]
Center, The American Genome [> >]
Rademakers, Rosa [> >]
Dalgard, Clifton L. [> >]
Boeve, Bradley F. [> >]
Beach, Thomas G. [> >]
Dickson, Dennis W. [> >]
Ross, Owen A. [> >]
Scholz, Sonja W. [> >]
Publication date : 10-Jul-2022
Journal title : Movement Disorders
Peer reviewed : Yes
Audience : International
Keywords : [en] Lewy body dementia (LBD) ; frontotemporal lobar degeneration (FTLD) ; GRN mutations ; progranulin ; neurodegeneration
Abstract : [en] ABSTRACT Background Loss-of-function mutations in GRN are a cause of familial frontotemporal dementia, and common variants within the gene have been associated with an increased risk of developing Alzheimer's disease and Parkinson's disease. Although TDP-43-positive inclusions are characteristic of GRN-related neurodegeneration, Lewy body copathology has also been observed in many GRN mutation carriers. Objective The objective of this study was to assess a Lewy body dementia (LBD) case–control cohort for pathogenic variants in GRN and to test whether there is an enrichment of damaging mutations among patients with LBD. Methods We analyzed whole-genome sequencing data generated for 2591 European-ancestry LBD cases and 4032 neurologically healthy control subjects to identify disease-causing mutations in GRN. Results We identified six heterozygous exonic GRN mutations in seven study participants (cases: n = 6; control subjects: n = 1). Each variant was predicted to be pathogenic or likely pathogenic. We found significant enrichment of GRN loss-of-function mutations in patients with LBD compared with control subjects (Optimized Sequence Kernel Association Test P = 0.0162). Immunohistochemistry in three definite LBD cases demonstrated Lewy body pathology and TDP-43-positive neuronal inclusions. Conclusions Our findings suggest that deleterious GRN mutations are a rare cause of familial LBD. © 2022 International Parkinson Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Research centres : Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)
Funders : Fonds National de la Recherche - FnR
Name of the research project : NCER-PD
Target : Researchers ; Professionals
Permalink : http://hdl.handle.net/10993/51636
DOI : 10.1002/mds.29144
Other URL : https://movementdisorders.onlinelibrary.wiley.com/doi/abs/10.1002/mds.29144
FnR project : FnR ; FNR11264123 > Rejko Krüger > NCER-PD > Ncer-pd > 01/01/2015 > 30/11/2020 > 2015