title: 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.
authors: 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.
authors: Stephan
authors: S
authors: Klebe
authors: Jean-Louis
authors: JL
authors: Golmard
authors: Michael A
authors: MA
authors: Nalls
authors: Mohamad
authors: M
authors: Saad
authors: Andrew B
authors: AB
authors: Singleton
authors: Jose M
authors: JM
authors: Bras
authors: John
authors: J
authors: Hardy
authors: Javier
authors: J
authors: Simon-Sanchez
authors: Peter
authors: P
authors: Heutink
authors: Gregor
authors: G
authors: Kuhlenbäumer
authors: Rim
authors: R
authors: Charfi
authors: Christine
authors: C
authors: Klein
authors: Johann
authors: J
authors: Hagenah
authors: Thomas
authors: T
authors: Gasser
authors: Isabel
authors: I
authors: Wurster
authors: Suzanne
authors: S
authors: Lesage
authors: Delia
authors: D
authors: Lorenz
authors: Günther
authors: G
authors: Deuschl
authors: Franck
authors: F
authors: Durif
authors: Pierre
authors: P
authors: Pollak
authors: Philippe
authors: P
authors: Damier
authors: François
authors: F
authors: Tison
authors: Alexandra
authors: A
authors: Durr
authors: Philippe
authors: P
authors: Amouyel
authors: Jean-Charles
authors: JC
authors: Lambert
authors: Christophe
authors: C
authors: Tzourio
authors: Cécilia
authors: C
authors: Maubaret
authors: Fanny
authors: F
authors: Charbonnier-Beaupel
authors: Khadija
authors: K
authors: Tahiri
authors: Marie
authors: M
authors: Vidailhet
authors: Maria
authors: M
authors: Martinez
authors: Alexis
authors: A
authors: Brice
authors: Jean-Christophe
authors: JC
authors: Corvol
mesh_terms: D017668:Age of Onset; D000368:Aged; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012737:Sex Factors
chemical_list: D002394:Catechol O-Methyltransferase
keywords: Movement Disorders; Neurogenetics; Parkinson's Disease