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J Neurol Neurosurg Psychiatry. 2013 Jun;84(6):666-73. doi: 10.1136/jnnp-2012-304475. Epub 2013 Feb 13.

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

Collaborators (156)

Agid Y, Anheim M, Bonnet AM, Borg M, Brice A, Broussolle E, Corvol JC, Damier P, Destée A, Durr A, Durif F, Klebe S, Lohmann E, Martinez M, Penet C, Pollak P, Krack P, Rascol O, Tison F, Tranchant C, Vérin M, Viallet F, Plagnol V, Bras JM, Hernandez DG, Sharma M, Sheerin UM, Saad M, Simón-Sánchez J, Schulte C, Lesage S, Sveinbjörnsdóttir S, Amouyel P, Arepalli S, Band G, Barker RA, Bellinguez C, Ben-Shlomo Y, Berendse HW, Berg D, Bhatia K, de Bie RM, Biffi A, Bloem B, Bochdanovits Z, Bonin M, Brockmann K, Brooks J, Burn DJ, Charlesworth G, Chen H, Chinnery PF, Chong S, Clarke CE, Cookson MR, Cooper JM, Corvol JC, Counsell C, Damier P, Dartigues JF, Deloukas P, Dexter DT, van Dijk KD, Dillman A, Durif F, Edkins S, Evans JR, Foltynie T, Freeman C, Gao J, Gardner M, Gibbs R, Goate A, Gray E, Guerreiro R, Gústafsson O, Harris C, Hellenthal G, van Hilten JJ, Hofman A, Hollenbeck A, Holton J, Hu M, Huang X, Huber H, Hudson G, Hunt SE, Huttenlocher J, Illig T, Jónsson PV, Langford C, Lees A, Lichtner P, Limousin P, Lopez G, Lorenz D, McNeill A, Moorby C, Morris H, Morrison KE, Mudanohwo E, O'Sullivan SS, Pearson J, Pearson R, Perlmutter JS, Pétursson H, Pirinen M, Pollak P, Post B, Potter S, Ravina B, Revesz T, Riess O, Rivadeneira F, Rizzu P, Ryten M, Sawcer S, Schapira A, Scheffer H, Shaw K, Shoulson I, Sidransky E, de Silva R, Smith C, Spencer CC, Stefánsson H, Steinberg S, Stockton JD, Strange A, Su Z, Talbot K, Tanner CM, Tashakkori-Ghanbaria A, Tison F, Trabzuni D, Traynor BJ, Uitterlinden G, Vandrovcova J, Velseboer D, Vidailhet M, Vukcevic D, Walker R, van de Warrenburg B, Weale ME, Wickremaratchi M, Williams N, Williams-Gray CH, Winder-Rhodes S, Martinez M, Donnelly P, Hardy J, Heutink P, Brice A, Gasser T, Wood NW, Singleton AB.

Author information

1
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.

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.

KEYWORDS:

Movement Disorders; Neurogenetics; Parkinson's Disease

PMID:
23408064
PMCID:
PMC3646288
DOI:
10.1136/jnnp-2012-304475
[Indexed for MEDLINE]
Free PMC Article

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