PT  - JOURNAL ARTICLE
AU  - Stephan Klebe
AU  - Jean-Louis Golmard
AU  - Michael A Nalls
AU  - Mohamad Saad
AU  - Andrew B Singleton
AU  - Jose M Bras
AU  - John Hardy
AU  - Javier Simon-Sanchez
AU  - Peter Heutink
AU  - Gregor Kuhlenbäumer
AU  - Rim Charfi
AU  - Christine Klein
AU  - Johann Hagenah
AU  - Thomas Gasser
AU  - Isabel Wurster
AU  - Suzanne Lesage
AU  - Delia Lorenz
AU  - Günther Deuschl
AU  - Franck Durif
AU  - Pierre Pollak
AU  - Philippe Damier
AU  - François Tison
AU  - Alexandra Durr
AU  - Philippe Amouyel
AU  - Jean-Charles Lambert
AU  - Christophe Tzourio
AU  - Cécilia Maubaret
AU  - Fanny Charbonnier-Beaupel
AU  - Khadija Tahiri
AU  - Marie Vidailhet
AU  - Maria Martinez
AU  - Alexis Brice
AU  - Jean-Christophe Corvol
AU  - French Parkinson's Disease Genetics Study Group and the International Parkinson's Disease Genomics Consortium (IPDGC)
TI  - The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism
AID  - 10.1136/jnnp-2012-304475
DP  - 2013 Jun 01
TA  - Journal of Neurology, Neurosurgery & Psychiatry
PG  - 666--673
VI  - 84
IP  - 6
4099  - http://jnnp.bmj.com/content/84/6/666.short
4100  - http://jnnp.bmj.com/content/84/6/666.full
SO  - J Neurol Neurosurg Psychiatry2013 Jun 01; 84
AB  - 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.