A rare truncating mutation in ADH1C (G78Stop) shows significant association with Parkinson disease in a large international sample.
BACKGROUND
Alcohol dehydrogenases (ADHs) may be involved in the pathogenesis of neurodegenerative disorders because of their multiple roles in detoxification pathways and retinoic acid synthesis. In a previous study, significant association of an ADH class IV allele with Parkinson disease (PD) was found in a Swedish sample.


METHODS
The previously associated single-nucleotide polymorphism plus 12 further polymorphisms in the ADH cluster on human chromosome 4q23 were screened for association in an extension of the original sample that now included 123 Swedish PD patients and 127 geographically matched control subjects. A rare nonsense single-nucleotide polymorphism in ADH1C (G78stop, rs283413) was identified in 3 of these patients but in no controls. To obtain sufficient power to detect a possible association of this rare variant with disease, we screened a large international sample of 1076 PD patients of European ancestry and 940 matched controls.


RESULTS
The previously identified association with an ADH class IV allele remained significant (P<.02) in the extended Swedish study. Furthermore, in the international collaboration, the G78stop mutation in ADH1C was found in 22 (2.0%) of the PD patients but only in 6 controls (0.6%). This association was statistically significant (chi(2)(1) = 7.5; 2-sided P = .007; odds ratio, 3.25 [95% confidence interval, 1.31-8.05]). In addition, the G78stop mutation was identified in 4 (10.0%) of 40 Caucasian index cases with PD with mainly hereditary forms of the disorder.


CONCLUSIONS
Findings presented herein provide further evidence for mutations in genes encoding ADHs as genetic risk factors for PD.
Buervenich
Silvia
S
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. buervens@intra.nimh.nih.gov
Carmine
Andrea
A
Galter
Dagmar
D
Shahabi
Haydeh N
HN
Johnels
Bo
B
Holmberg
Björn
B
Ahlberg
Jarl
J
Nissbrandt
Hans
H
Eerola
Johanna
J
Hellström
Olli
O
Tienari
Pentti J
PJ
Matsuura
Tohru
T
Ashizawa
Tetsuo
T
Wüllner
Ullrich
U
Klockgether
Thomas
T
Zimprich
Alexander
A
Gasser
Thomas
T
Hanson
Melissa
M
Waseem
Shamaila
S
Singleton
Andrew
A
McMahon
Francis J
FJ
Anvret
Maria
M
Sydow
Olof
O
Olson
Lars
L
D000328:Adult; D000368:Aged; D000426:Alcohol Dehydrogenase / Q000737:chemistry / Q000145:classification / Q000235:genetics*; D000483:Alleles; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D018388:Codon, Terminator / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044465:White People
D018388:Codon, Terminator; D000426:Alcohol Dehydrogenase