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A Rare Truncating Mutation in ADH1C (G78Stop) Shows Significant Association With Parkinson Disease in a Large International Sample
Silvia Buervenich, PhD;
Andrea Carmine, PhD;
Dagmar Galter, PhD;
Haydeh N. Shahabi, MS;
Bo Johnels, MD, PhD;
Björn Holmberg, MD, PhD;
Jarl Ahlberg, MD;
Hans Nissbrandt, MD, PhD;
Johanna Eerola, MD;
Olli Hellström, MD;
Pentti J. Tienari, MD, PhD;
Tohru Matsuura, MD;
Tetsuo Ashizawa, MD;
Ullrich Wüllner, MD;
Thomas Klockgether, MD;
Alexander Zimprich, MD;
Thomas Gasser, MD;
Melissa Hanson, MS;
Shamaila Waseem, MD;
Andrew Singleton, PhD;
Francis J. McMahon, MD;
Maria Anvret, PhD;
Olof Sydow, MD, PhD;
Lars Olson, PhD
Arch Neurol. 2005;62:74-78.
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.
Patients 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 ( 21 = 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.
Conclusion Findings presented herein provide further evidence for mutations in genes encoding ADHs as genetic risk factors for PD.
Author Affiliations: Department of Neuroscience (Drs Buervenich, Carmine, Galter, and Olson), Department of Molecular Medicine, Clinical Neurogenetics Unit (Dr Anvret), and Department of Clinical Neuroscience, Neurology Section (Dr Sydow), Karolinska Institutet, Stockholm, Sweden; Mood and Anxiety Disorders Program, Genetics Unit, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Md (Drs Buervenich and McMahon); Departments of Pharmacology (Ms Shahabi and Dr Nissbrandt) and Clinical Neurosciences (Drs Johnels, Holmberg, and Ahlberg), Göteborg University, Göteborg, Sweden; Department of Neurology, University of Helsinki, Helsinki (Drs Eerola and Tienari), and Seinäjoki Central Hospital, Seinäjoki (Dr Hellström), Finland; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex (Dr Matsuura); Department of Neurology, The University of Texas Medical Branch, Galveston (Dr Ashizawa); Department of Neurology, University of Bonn, Bonn (Drs Wüllner and Klockgether), and Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen (Drs Zimprich and Gasser), Germany; Laboratory of Neurogenetics (Ms Hanson) and Molecular Genetics Section (Drs Waseem and Singleton), National Institute on Aging, National Institutes of Health; AstraZeneca R&D Södertälje, Södertälje, Sweden (Dr Anvret).
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