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

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.

DOI: 10.1136/jnnp-2012-304475

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@inproceedings{Klebe2013TheVC, title={The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism}, author={Stephan Klebe and Jean-Louis Golmard and Michael A. Nalls and Mohamad Firdaus Mat Saad and Andrew Singleton and Jos{\'e} Br{\'a}s and John Hardy and Javier Sim{\'o}n-S{\'a}nchez and Peter Heutink and Gregor Kuhlenbaeumer and Rim Charfi and Christine Klein and Johann Hagenah and Thomas Gasser and Isabel Wurster and Suzanne R Lesage and Delia Lorenz and G{\"{u}nther Deuschl and Franck Durif and Pierre Pollak and Philippe Damier and Francois Tison and Alexandra Durr and Philippe Amouyel and Jean-Charles Lambert and Christophe Tzourio and C{\'e}cilia G. Maubaret and Fanny Charbonnier-Beaupel and Khadija Tahiri and Marie Vidailhet and Maria Martinez and Alexis Brice and Jean-Christophe Corvol and Yves Agid and Mathieu Anheim and A-M Bonnet and Michel Borg and Emmanuel Broussolle and Ph. Damier and Alain Dest{\'e}e and Ebba Lohmann and M Martinez and Christiane Penet and Paul Krack and Olivier Rascol and Christine Tranchant and Marc V{\'e}rin and François Viallet and Vincent Plagnol and Dena G. Hernandez and Manu S Sharma and Una-Marie Sheerin and Claudia C Schulte and Sigurlaug Sveinbj{\"{o}rnsd{\'o}ttir and Sampath K Arepalli and Gavin Band and Roger A. Barker and C{\'e}line Bellinguez and Y Ben-Shlomo and Henk W. Berendse and Daniela Berg and Kailash P Bhatia and Rob M. A. de Bie and Alessandro Biffi and Bas R. Bloem and Zolt{\'a}n Bochdanovits and Michael Bonin and Kathrin Brockmann and Janet A Brooks and David J. Burn and Gavin Charlesworth and Honglei Chen and Patrick F. Chinnery and Sean B Chong and Carl E. Clarke and Mark Robert Cookson and J. M. Cooper and Jean Christophe Corvol and Carl E. Counsell and Jean-François Dartigues and Panagiotis Deloukas and David T Dexter and Karin D. van Dijk and Allissa A. Dillman and Frank Durif and Sarah J Edkins and Jonathan R. Evans and Thomas Foltynie and Colin Freeman and Jianjun Gao and Michelle Gardner and Raphael J. Gibbs and Alison M. Goate and Emma H. Gray and R Guerreiro and {\'O}mar G{\'u}stafsson and Clare E Harris and Garrett Hellenthal and Jacobus Johannes van Hilten and Albert Hofman and Albert R . Hollenbeck and J. L. Holton and Michele T. M. Hu and Xuemei Huang and Heiko S Huber and Gavin Hudson and Sarah E. Hunt and Johanna Huttenlocher and Thomas Illig and Palmi V. Jonsson and Cordelia Langford and A. J. Lees and Peter C. Lichtner and Patricia Limousin and Grisel J Lopez and Alisdair McNeill and Catriona Moorby and Huw R Morris and Karen E. Morrison and Ese E. Mudanohwo and Sean Stephen O'Sullivan and Justin Pearson and Richard D. Pearson and Joel S. Perlmutter and Hj{\"{o}rvar P{\'e}tursson and Matti Pirinen and Bart Post and Simon C. Potter and Bernard M. Ravina and Tamas R Revesz and Olaf Riess and Fernando Rivadeneira and Patrizia Rizzu and Mina Ryten and Stephen J Sawcer and Anthony H V Schapira and H. Scheffer and Karen Shaw and Ira Shoulson and Ellen Sidransky and Rohan de Silva and Colin M. Smith and Chris C A Spencer and Hreinn Stefansson and Stacy Steinberg and Joanna D. Stockton and Amy Strange and Zhan Su and Kevin Talbot and Carlie M. Tanner and Avazeh Tashakkori-Ghanbaria and Daniah Trabzuni and Bryan J. Traynor and G. Uitterlinden and Jana Vandrovcova and Daan C Velseboer and Damjan Vukcevic and Robert Walker and Bart P. C. van de Warrenburg and Michael E. Weale and Mirdhu M Wickremaratchi and Nigel Williams and Caroline H. Williams-Gray and Sophie E. Winder-Rhodes and Peter Donnelly and Nicholas W. Wood}, booktitle={Journal of neurology, neurosurgery, and psychiatry}, year={2013} }