Article (Scientific journals)
Single-cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene.
Elstner, Matthias; Morris, Christopher M.; Heim, Katharina et al.
2009In Annals of Neurology, 66 (6), p. 792-8
Peer Reviewed verified by ORBi
 

Files


Full Text
Elstner.pdf
Publisher postprint (544.95 kB)
Request a copy

All documents in ORBilu are protected by a user license.

Send to



Details



Keywords :
Aged; Case-Control Studies; Cohort Studies; Dopamine/metabolism; England; Female; Gene Expression Profiling; Gene Frequency; Genetic Predisposition to Disease; Genotype; Germany; Humans; Italy; Male; Middle Aged; Neurons/metabolism; Oligonucleotide Array Sequence Analysis; Parkinson Disease/enzymology/genetics/pathology; Polymorphism, Single Nucleotide/genetics; Pyridoxal Kinase/genetics; Substantia Nigra/pathology
Abstract :
[en] OBJECTIVE: The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined. METHODS: We carried out whole-genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single-nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts. RESULTS: We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 x 10(-7)), PDXK (vitamin B6/dopamine metabolism, p = 3.27 x 10(-6)), SRGAP3 (axon guidance, p = 5.65 x 10(-6)), and TRAPPC4 (vesicle transport, p = 5.81 x 10(-6)). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 x 10(-7) (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18-1.44). INTERPRETATION: We provide an example of how microgenomic genome-wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
Elstner, Matthias
Morris, Christopher M.
Heim, Katharina
Lichtner, Peter
Bender, Andreas
Mehta, Divya
Schulte, Claudia
Sharma, Manu
Hudson, Gavin
Goldwurm, Stefano
Giovanetti, Alessandro
Zeviani, Massimo
Burn, David J.
McKeith, Ian G.
Perry, Robert H.
Jaros, E.
Krüger, Rejko ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Wichmann, H.-Erich
Schreiber, Stefan
Campbell, Harry
Wilson, James F.
Wright, Alan F.
Dunlop, Malcolm
Pistis, Giorgio
Toniolo, Daniela
Chinnery, Patrick F.
Gasser, Thomas
Klopstock, Thomas
Meitinger, Thomas
Prokisch, Holger
Turnbull, Douglass M.
More authors (21 more) Less
Language :
English
Title :
Single-cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene.
Publication date :
2009
Journal title :
Annals of Neurology
ISSN :
1531-8249
Publisher :
John Wiley & Sons, Hoboken, United States - New York
Volume :
66
Issue :
6
Pages :
792-8
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 28 June 2014

Statistics


Number of views
113 (6 by Unilu)
Number of downloads
1 (1 by Unilu)

Scopus citations®
 
44
Scopus citations®
without self-citations
38
OpenCitations
 
39
WoS citations
 
39

Bibliography


Similar publications



Contact ORBilu