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Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene
Author(s) -
Elstner Matthias,
Morris Christopher M.,
Heim Katharina,
Lichtner Peter,
Bender Andreas,
Mehta Divya,
Schulte Claudia,
Sharma Manu,
Hudson Gavin,
Goldwurm Stefano,
Giovanetti Alessandro,
Zeviani Massimo,
Burn David J.,
McKeith Ian G.,
Perry Robert H.,
Jaros E.,
Krüger Rejko,
Wichmann H.Erich,
Schreiber Stefan,
Campbell Harry,
Wilson James F.,
Wright Alan F.,
Dunlop Malcolm,
Pistis Giorgio,
Toniolo Daniela,
Chinnery Patrick F.,
Gasser Thomas,
Klopstock Thomas,
Meitinger Thomas,
Prokisch Holger,
Turnbull Douglass M.
Publication year - 2009
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21780
Subject(s) - genome wide association study , single nucleotide polymorphism , substantia nigra , genetic association , odds ratio , biology , dopaminergic , lrrk2 , genetics , parkinson's disease , disease , bioinformatics , medicine , genotype , gene , endocrinology , dopamine
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. Ann Neurol 2009;66:792–798