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

TitleSingle-cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene.
Publication TypeJournal Article
Year of Publication2009
AuthorsElstner, M, Morris, CM, Heim, K, Lichtner, P, Bender, A, Mehta, D, Schulte, C, Sharma, M, Hudson, G, Goldwurm, S, Giovanetti, A, Zeviani, M, Burn, DJ, McKeith, IG, Perry, RH, Jaros, E, Krüger, R, Wichmann, H-E, Schreiber, S, Campbell, H, Wilson, JF, Wright, AF, Dunlop, M, Pistis, G, Toniolo, D, Chinnery, PF, Gasser, T, Klopstock, T, Meitinger, T, Prokisch, H, Turnbull, DM
JournalAnn Neurol
Date Published2009 Dec
KeywordsAged, Case-Control Studies, Cohort Studies, Dopamine, England, Female, Gene Expression Profiling, Gene Frequency, Genetic Predisposition to Disease, Genotype, Germany, Humans, Italy, Male, Middle Aged, Neurons, Oligonucleotide Array Sequence Analysis, Parkinson Disease, Polymorphism, Single Nucleotide, Pyridoxal Kinase, Substantia Nigra

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.

Alternate JournalAnn. Neurol.
Citation Key10.1002/ana.21780
PubMed ID20035503
PubMed Central IDPMC4034432
Grant ListCZB/4/710 / / Chief Scientist Office / United Kingdom
084980 / / Wellcome Trust / United Kingdom
MC_U127561128 / / Medical Research Council / United Kingdom
G0900652 / / Medical Research Council / United Kingdom
G0502157 / / Medical Research Council / United Kingdom
G0400074 / / Medical Research Council / United Kingdom
GTB07001 / / Telethon / Italy
G-0618 / / Parkinson's UK / United Kingdom
074454 / / Wellcome Trust / United Kingdom