The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism

Stephan Klebe, Jean Louis Golmard, Michael A. Nalls, Mohamad Saad, Andrew B. Singleton, Jose M. Bras, John Hardy, Javier Simon-Sanchez, Peter Heutink, Gregor Kuhlenbäumer, Rim Charfi, Christine Klein, Johann Hagenah, Thomas Gasser, Isabel Wurster, Suzanne Lesage, Delia Lorenz, Günther Deuschl, Franck Durif, Pierre PollakPhilippe Damier, François Tison, Alexandra Durr, Philippe Amouyel, Jean Charles Lambert, Christophe Tzourio, Cécilia Maubaret, Fanny Charbonnier-Beaupel, Khadija Tahiri, Marie Vidailhet, Maria Martinez, Alexis Brice, Jean Christophe Corvol, Y. Agid, M. Anheim, A. M. Bonnet, M. Borg, A. Brice, E. Broussolle, J. C. Corvol, Ph Damier, A. Destée, F. Durif, S. Klebe, E. Lohmann, M. Martinez, C. Penet, P. Pollak, P. Krack, O. Rascol, F. Tison, C. Tranchant, M. Vérin, F. Viallet, M. Vidailhet, Michael A. Nalls, Vincent Plagnol, Jose M. Bras, Dena G. Hernandez, Manu Sharma, Una Marie Sheerin, Claudia Schulte, Sigurlaug Sveinbjörnsdóttir, Sampath Arepalli, Gavin Band, Damjan Vukcevic, Roger A. Barker, Céline Bellinguez, Yoav Ben-Shlomo, Henk W. Berendse, Daniela Berg, Kailash Bhatia, Rob M.A. De Bie, Alessandro Biffi, Bas Bloem, Zoltan Bochdanovits, Michael Bonin, Kathrin Brockmann, Janet Brooks, David J. Burn, Gavin Charlesworth, Honglei Chen, Patrick F. Chinnery, Sean Chong, Carl E. Clarke, Mark R. Cookson, J. Mark Cooper, Jean Christophe Corvol, Carl Counsell, Jean François Dartigues, Panos Deloukas, David T. Dexter, Karin D. Van Dijk, Allissa Dillman, Frank Durif, Sarah Edkins, Jonathan R. Evans, Thomas Foltynie, Colin Freeman, Jianjun Gao, Michelle Gardner, Raphael Gibbs, Alison Goate, Emma Gray, Rita Guerreiro, Ómar Gústafsson, Clare Harris, Garrett Hellenthal, Jacobus J. Van Hilten, Albert Hofman, Albert Hollenbeck, Janice Holton, Michele Hu, Xuemei Huang, Heiko Huber, Gavin Hudson, Sarah E. Hunt, Johanna Huttenlocher, Thomas Illig, Pálmi V. Jónsson, Cordelia Langford, Andrew Lees, Peter Lichtner, Patricia Limousin, Grisel Lopez, Alisdair McNeill, Catriona Moorby, Matthew Moore, Huw Morris, Karen E. Morrison, Ese Mudanohwo, Sean S. O'Sullivan, Justin Pearson, Richard Pearson, Joel S. Perlmutter, Hjörvar Pétursson, Matti Pirinen, Bart Post, Bernard Ravina, Tamas Revesz, Olaf Riess, Fernando Rivadeneira, Patrizia Rizzu, Mina Ryten, Stephen Sawcer, Anthony Schapira, Hans Scheffer, Karen Shaw, Ira Shoulson, Ellen Sidransky, Rohan De Silva, Colin Smith, Chris C.A. Spencer, Hreinn Stefánsson, Stacy Steinberg, Joanna D. Stockton, Amy Strange, Zhan Su, Kevin Talbot, Carlie M. Tanner, Avazeh Tashakkori-Ghanbaria, Daniah Trabzuni, Bryan J. Traynor, André G. Uitterlinden, Jana Vandrovcova, Daan Velseboer, Vidailhet Marie Vidailhet, Robert Walker, Bart Van De Warrenburg, Michael E. Weale, Mirdhu Wickremaratchi, Nigel Williams, Caroline H. Williams-Gray, Sophie Winder-Rhodes, Kári Stefánsson, Nicholas W. Wood, Andrew B. Singleton

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls ( p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.

Original languageEnglish (US)
Pages (from-to)666-673
Number of pages8
JournalJournal of Neurology, Neurosurgery and Psychiatry
Volume84
Issue number6
DOIs
StatePublished - Jun 1 2013

All Science Journal Classification (ASJC) codes

  • Surgery
  • Clinical Neurology
  • Psychiatry and Mental health

Fingerprint Dive into the research topics of 'The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism'. Together they form a unique fingerprint.

  • Cite this

    Klebe, S., Golmard, J. L., Nalls, M. A., Saad, M., Singleton, A. B., Bras, J. M., Hardy, J., Simon-Sanchez, J., Heutink, P., Kuhlenbäumer, G., Charfi, R., Klein, C., Hagenah, J., Gasser, T., Wurster, I., Lesage, S., Lorenz, D., Deuschl, G., Durif, F., ... Singleton, A. B. (2013). The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism. Journal of Neurology, Neurosurgery and Psychiatry, 84(6), 666-673. https://doi.org/10.1136/jnnp-2012-304475