title: Single-cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Elstner
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Morris
authors.forename: Katharina
authors.initials: K
authors.lastname: Heim
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.forename: Divya
authors.initials: D
authors.lastname: Mehta
authors.forename: Claudia
authors.initials: C
authors.lastname: Schulte
authors.forename: Manu
authors.initials: M
authors.lastname: Sharma
authors.forename: Gavin
authors.initials: G
authors.lastname: Hudson
authors.forename: Stefano
authors.initials: S
authors.lastname: Goldwurm
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giovanetti
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.forename: David J
authors.initials: DJ
authors.lastname: Burn
authors.forename: Ian G
authors.initials: IG
authors.lastname: McKeith
authors.forename: Robert H
authors.initials: RH
authors.lastname: Perry
authors.forename: E
authors.initials: E
authors.lastname: Jaros
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.forename: Malcolm
authors.initials: M
authors.lastname: Dunlop
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pistis
authors.forename: Daniela
authors.initials: D
authors.lastname: Toniolo
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D015331:Cohort Studies; D004298:Dopamine / Q000378:metabolism*; D004739:England; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011731:Pyridoxal Kinase / Q000235:genetics*; D013378:Substantia Nigra / Q000473:pathology*
chemical_list: D011731:Pyridoxal Kinase; D004298:Dopamine