Reference : GRN Mutations Are Associated with Lewy Body Dementia

	Document type :	Scientific journals : Article
	Discipline(s) :	Life sciences : Genetics & genetic processes Human health sciences : Neurology
	Focus Areas :	Systems Biomedicine
	To cite this reference:	http://hdl.handle.net/10993/51636

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

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