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Elstner, M. ; Morris, C.M.* ; Heim, K. ; Lichtner, P. ; Bender, A.* ; Mehta, D. ; Schulte, C.* ; Sharma, M.* ; Hudson, G.* ; Goldwurm, S.* ; Giovanetti, A.* ; Zeviani, M.* ; Burn, D.J.* ; McKeith, I.G.* ; Perry, R.H.* ; Jaros, E.* ; Kruger, R.* ; Wichmann, H.-E. ; Schreiber, S.* ; Campbell, H.* ; Wilson, J.F.* ; Wright, A.F.* ; Dunlop, M.* ; Pistis, G.* ; Toniolo, D.* ; Chinnery, P.F.* ; Gasser, T.* ; Klopstock, T.* ; Meitinger, T. ; Prokisch, H. ; Turnbull, D.M.*

Single-cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene.

Ann. Neurol. 66, 792-798 (2009)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords genomic convergence; sunstantia-nigra; candidate genes; axon guidance; risk; pathway; reveals
Language
Publication Year 2009
HGF-reported in Year 2009
ISSN (print) / ISBN 0364-5134
e-ISSN 1531-8249
Journal Annals of Neurology
Quellenangaben Volume: 66, Issue: 6, Pages: 792-798 Article Number: , Supplement: ,
Publisher Wiley
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
Institute of Epidemiology (EPI)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health

30503 - Chronic Diseases of the Lung and Allergies
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500700-001
G-500700-003
G-503900-001
DOI 10.1002/ana.21780
Scopus ID 73549090994
PubMed ID 20035503
Erfassungsdatum 2009-12-31
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