Single-cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene.
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.
Elstner
Matthias
M
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Morris
Christopher M
CM
Heim
Katharina
K
Lichtner
Peter
P
Bender
Andreas
A
Mehta
Divya
D
Schulte
Claudia
C
Sharma
Manu
M
Hudson
Gavin
G
Goldwurm
Stefano
S
Giovanetti
Alessandro
A
Zeviani
Massimo
M
Burn
David J
DJ
McKeith
Ian G
IG
Perry
Robert H
RH
Jaros
E
E
Krüger
Rejko
R
Wichmann
H-Erich
HE
Schreiber
Stefan
S
Campbell
Harry
H
Wilson
James F
JF
Wright
Alan F
AF
Dunlop
Malcolm
M
Pistis
Giorgio
G
Toniolo
Daniela
D
Chinnery
Patrick F
PF
Gasser
Thomas
T
Klopstock
Thomas
T
Meitinger
Thomas
T
Prokisch
Holger
H
Turnbull
Douglass M
DM
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*
D011731:Pyridoxal Kinase; D004298:Dopamine