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

Stephan Klebe (1) , Jean-Louis Golmard (2) , Michael A Nalls (3) , Mohamad Saad , Andrew B Singleton (4) , Jose M Bras , John Hardy (5) , Javier Simon-Sanchez (4) , Peter Heutink (4) , Gregor Kuhlenbäumer (6) , Rim Charfi , Christine Klein , Johann Hagenah (7) , Thomas Gasser , Isabel Wurster , Suzanne Lesage (8) , Delia Lorenz , Günther Deuschl (9) , Franck Durif (10) , Pierre Pollak , Philippe Damier , François Tison (11) , Alexandra Durr (8) , Philippe Amouyel (12) , Jean-Charles Lambert , Christophe Tzourio (13) , Cécilia Maubaret (14) , Fanny Charbonnier-Beaupel , Khadija Tahiri (8) , Marie Vidailhet (15, 8) , Maria Martinez (16) , Alexis Brice (8) , Jean-Christophe Corvol (15, 8)

1 INSERM UMR_S9745
2 Département de Biostatistiques [Paris]
3 UCL Institute of neurology
4 Department of Clinical Genetics
5 UNIROUEN UFR Santé - UNIROUEN - UFR Santé
6 Institute of Experimental Medicine
7 Department of Neurology, University of Lübeck
8 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
9 Department of Neurology
10 NPsy-Sydo - Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux
11 IMN - Institut des Maladies Neurodégénératives [Bordeaux]
12 Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations
13 Service de neurologie [Univ. Paris VII]
14 Epidémiologie et Biostatistique [Bordeaux]
15 Service de Neurologie [CHU Pitié-Salpêtrière]
16 Departamento de Geologia CICESE

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.

Domains: Life Sciences [q-bio]

Stephan Klebe, Jean-Louis Golmard, Michael A Nalls, Mohamad Saad, Andrew B Singleton, et al.. 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, 2013, 84 (6), pp.666-73. ⟨10.1136/jnnp-2012-304475⟩. ⟨hal-01133853⟩