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

Matthias Elstner, Christopher M. Morris, Katharina Heim, Peter Lichtner, Andreas Bender, Divya Mehta, Claudia Schulte, Manu Sharma, Gavin Hudson, Stefano Goldwurm, Alessandro Giovanetti, Massimo Zeviani, David J. Burn, Ian G. McKeith, Robert H. Perry, E. Jaros, Rejko Krueger, H. -Erich Wichmann, Stefan Schreiber, Harry CampbellJames F. Wilson, Alan F. Wright, Malcolm Dunlop, Giorgio Pistis, Daniela Toniolo, Patrick F. Chinnery, Thomas Gasser, Thomas Klopstock, Thomas Meitinger, Holger Prokisch, Douglass M. Turnbull

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 < 10(-6)), and X 10-6). 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. Ann Neurol 2009;66:792-798

Original languageEnglish
Pages (from-to)792-798
Number of pages7
JournalAnnals of Neurology
Issue number6
Publication statusPublished - Dec 2009


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