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Research paper
The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism
  1. Stephan Klebe1,2,3,4,5,6,7,
  2. Jean-Louis Golmard8,
  3. Michael A Nalls9,
  4. Mohamad Saad10,11,
  5. Andrew B Singleton9,
  6. Jose M Bras12,
  7. John Hardy12,
  8. Javier Simon-Sanchez9,13,
  9. Peter Heutink13,
  10. Gregor Kuhlenbäumer14,
  11. Rim Charfi15,16,
  12. Christine Klein17,
  13. Johann Hagenah17,
  14. Thomas Gasser18,19,
  15. Isabel Wurster18,19,
  16. Suzanne Lesage1,2,3,
  17. Delia Lorenz20,
  18. Günther Deuschl20,
  19. Franck Durif21,
  20. Pierre Pollak22,
  21. Philippe Damier23,
  22. François Tison24,
  23. Alexandra Durr1,2,3,4,
  24. Philippe Amouyel25,26,27,
  25. Jean-Charles Lambert25,26,27,
  26. Christophe Tzourio28,29,
  27. Cécilia Maubaret30,
  28. Fanny Charbonnier-Beaupel1,2,3,
  29. Khadija Tahiri1,2,3,
  30. Marie Vidailhet2,3,6,31,
  31. Maria Martinez10,11,
  32. Alexis Brice1,2,3,4,6,
  33. Jean-Christophe Corvol1,2,3,5,15,
  34. French Parkinson's Disease Genetics Study Group and the International Parkinson's Disease Genomics Consortium (IPDGC)
  1. 1INSERM, UMR_S975, CR-ICM, Paris, France
  2. 2UPMC University Paris 06, UMR_S975, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France
  3. 3CNRS UMR 7225, CR-ICM, Pitié-Salpêtrière Hospital, Paris, France
  4. 4Assitance Publique Hôpitaux de Paris, Département de Génétique et Cytogénétique, Hôpital de la Pitié-Salpêtrière, Paris, France
  5. 5INSERM, CIC-9503, Hôpital de la Pitié-Salpêtrière, Paris, France
  6. 6Assistance Publique Hôpitaux de Paris, Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France
  7. 7Department of Neurology, University Hospital Würzburg, Würzburg, Germany
  8. 8Assistance Publique Hôpitaux de Paris, Department of Biostatistics, Hôpital de la Pitié-Salpêtrière, Paris, France
  9. 9Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda Maryland, USA
  10. 10INSERM U1043, CPTP, Toulouse, France
  11. 11Paul Sabatier University, Toulouse, France
  12. 12Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
  13. 13Department of Clinical Genetics Section of Medical Genomics, VU Medical Center, Amsterdam, Netherlands
  14. 14Institute of Experimental Medicine, Christian-Albrechts University, Kiel, Germany
  15. 15Assistance Publique Hôpitaux de Paris, Department of Pharmacology, Hôpital de la Pitié-Salpêtrière, Paris, France
  16. 16Faculté de Médecine de Tunis, Université de Tunis El Manar, Centre National de Pharmacovigilance de Tunis, Service de Pharmacologie Clinique, Tunis, Tunisia
  17. 17Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
  18. 18Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
  19. 19Department of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
  20. 20Department of Neurology, UKS-H, Campus Kiel; Christian-Albrechts-University, Kiel, Germany
  21. 21Hôpital Gabriel Montpied, CHU de Grenoble, Department of Neurology, Clermont-Ferrand, France
  22. 22CHU de Grenoble, Department of Neurology, Grenoble, France
  23. 23CHU de Nantes, Centre d'Investigation Clinique, Nantes, France
  24. 24 Hôpital Haut-Lévêque, Department of Neurology, Pessac, France
  25. 25INSERM, U744, Lille, France
  26. 26Institut Pasteur de Lille, Lille, France
  27. 27Université Lille-Nord de France, Lille, France
  28. 28Université Pierre et Marie Curie—Paris 6, CNRS 7225 CRICM, ER4-UPMC Modélisation en recherche clinique, Hôpital Pitié-Salpêtrière, Paris, France
  29. 29INSERM UMR_S708, Neuroépidémiologie, Paris, France
  30. 30INSERM U897, Université Bordeaux Ségalen, Bordeaux, France
  31. 31“Movement Disorders and Basal Ganglia: Pathophysiology and experimental Therapeutics”, INSERM, UMR_S975, Paris, France
  1. Correspondence to Dr Jean-Christophe Corvol, Centre d'Investigation Clinique, Institut du Cerveau et de la Moelle épinière, Hôpital de la Pitié-Salpêtrière, 47 boulevard de l'Hôpital, Paris 75651 Cedex 13, France; jean-christophe.corvol{at}psl.aphp.fr.

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.

  • Movement Disorders
  • Neurogenetics
  • Parkinson's Disease

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