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

Lookup NU author(s): Dr Matthias Elstner, Dr Christopher Morris, Professor Gavin Hudson, Professor David Burn, Professor Ian McKeith, Emeritus Professor Robert Perry, Dr Evelyn Jaros, Professor Patrick Chinnery, Emeritus Professor Doug Turnbull


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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 × 10-7), PDXK (vitamin B6/dopamine metabolism, p = 3.27 × 10-6), SRGAP3 (axon guidance, p = 5.65 × 10 -6), and TRAPPC4 (vesicle transport, p = 5.81 × 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 × 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. © 2009 American Neurological Association.

Publication metadata

Author(s): Elstner M, Morris C, Heim K, Lichtner P, Bender A, Mehta D, Schulte C, Sharma M, Hudson G, Goldwurm S, Giovanetti A, Zeviani M, Burn D, McKeith I, Perry R, Jaros E, Krüger R, Wichmann H, Schreiber S, Campbell H, Wilson J, Wright A, Dunlop M, Pistis G, Toniolo D, Chinnery P, Gasser T, Klopstock T, Meitinger T, Prokisch H, Turnbull D

Publication type: Article

Publication status: Published

Journal: Annals of Neurology

Year: 2009

Volume: 66

Issue: 6

Pages: 792-798

Print publication date: 01/12/2009

Online publication date: 18/06/2009

Acceptance date: 09/06/2009

ISSN (print): 0364-5134

ISSN (electronic): 1531-8249

Publisher: John Wiley & Sons, Inc.


DOI: 10.1002/ana.21780

PubMed id: 20035503


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Funder referenceFunder name
European Neurological Society
Health Protection Agency UK
Wellcome Trust/UK
German National Genome Network of the German Ministry for Education and Research (NGFNplus)
Newcastle University Centre for Brain Ageing and Vitality
HA-215Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in ail Ageing Society