Potential conflict of interest: Nothing to report.
Single-cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene†
Article first published online: 18 JUN 2009
Copyright © 2009 American Neurological Association
Annals of Neurology
Volume 66, Issue 6, pages 792–798, December 2009
How to Cite
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., Krüger, 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. and Turnbull, D. M. (2009), Single-cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene. Ann Neurol., 66: 792–798. doi: 10.1002/ana.21780
- Issue published online: 23 DEC 2009
- Article first published online: 18 JUN 2009
- Accepted manuscript online: 18 JUN 2009 12:00AM EST
- Manuscript Revised: 9 JUN 2009
- Manuscript Accepted: 9 JUN 2009
- Manuscript Received: 10 JAN 2009
- European Neurological Society
- Wellcome Trust/UK
- Impulse and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society. Grant Number: HA-215
- German National Genome Network of the German Ministry for Education and Research (NGFNplus)
- Health Protection Agency UK
- Newcastle University Centre for Brain Ageing and Vitality
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.
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.
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).
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. Ann Neurol 2009;66:792–798