The University of Southampton
University of Southampton Institutional Repository

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

The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism
The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism
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.
1468-330X
666-673
Klebe, S.
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Golmard, J.-L.
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Nalls, M.A.
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Saad, M.
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Singleton, A.B.
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Bras, J.M.
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Hardy, J.
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Simon-Sanchez, J.
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Heutink, P.
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Kuhlenbaumer, G.
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de Silva, R.
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Klebe, S., Golmard, J.-L. and Nalls, M.A. et al. (2013) 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, 84 (6), 666-673. (doi:10.1136/jnnp-2012-304475).

Record type: Article

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.

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Accepted/In Press date: 7 January 2013
e-pub ahead of print date: 13 February 2013
Organisations: Medical Education

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Local EPrints ID: 398462
URI: http://eprints.soton.ac.uk/id/eprint/398462
ISSN: 1468-330X
PURE UUID: 3d8bb7f3-2d60-4407-80ca-0cd55f5c43a3
ORCID for K.E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 25 Jul 2016 13:44
Last modified: 10 Dec 2019 01:32

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Author: S. Klebe
Author: J.-L. Golmard
Author: M.A. Nalls
Author: M. Saad
Author: A.B. Singleton
Author: J.M. Bras
Author: J. Hardy
Author: J. Simon-Sanchez
Author: P. Heutink
Author: G. Kuhlenbaumer
Author: R. Charfi
Author: C. Klein
Author: J. Hagenah
Author: T. Gasser
Author: I. Wurster
Author: S. Lesage
Author: D. Lorenz
Author: G. Deuschl
Author: F. Durif
Author: P. Pollak
Author: P. Damier
Author: F. Tison
Author: A. Durr
Author: P. Amouyel
Author: J.-C. Lambert
Author: C. Tzourio
Author: C. Maubaret
Author: F. Charbonnier-Beaupel
Author: K. Tahiri
Author: M. Vidailhet
Author: M. Martinez
Author: A. Brice
Author: J.-C. Corvol
Author: Y. Agid
Author: M. Anheim
Author: A.-M. Bonnet
Author: M. Borg
Author: E. Broussolle
Author: A. Destee
Author: E. Lohmann
Author: C. Penet
Author: P. Krack
Author: O. Rascol
Author: C. Tranchant
Author: M. Verin
Author: F. Viallet
Author: V. Plagnol
Author: D.G. Hernandez
Author: M. Sharma
Author: U.-M. Sheerin
Author: C. Schulte
Author: S. Sveinbjornsdottir
Author: S. Arepalli
Author: G. Band
Author: R. A. Barker
Author: C. Bellinguez
Author: Y. Ben-Shlomo
Author: H.W. Berendse
Author: D. Berg
Author: K. Bhatia
Author: R.M. de Bie
Author: A. Biffi
Author: B. Bloem
Author: Z. Bochdanovits
Author: M. Bonin
Author: K. Brockmann
Author: J. Brooks
Author: D.J. Burn
Author: G. Charlesworth
Author: H. Chen
Author: P.F. Chinnery
Author: S. Chong
Author: C.E. Clarke
Author: M.R. Cookson
Author: J.M. Cooper
Author: J.C. Corvol
Author: C. Counsell
Author: J.-F. Dartigues
Author: P. Deloukas
Author: D.T. Dexter
Author: K.D. van Dijk
Author: A. Dillman
Author: S. Edkins
Author: J.R. Evans
Author: T. Foltynie
Author: C. Freeman
Author: J. Gao
Author: M. Gardner
Author: R. Gibbs
Author: A. Goate
Author: E. Gray
Author: R. Guerreiro
Author: O. Gustafsson
Author: C. Harris
Author: G. Hellenthal
Author: J.J. van Hilten
Author: A. Hofman
Author: A. Hollenbeck
Author: J. Holton
Author: M. Hu
Author: X. Huang
Author: H. Huber
Author: G. Hudson
Author: S.E. Hunt
Author: J. Huttenlocher
Author: T. Illig
Author: P.V. Jonsson
Author: C. Langford
Author: A. Lees
Author: P. Lichtner
Author: P. Limousin
Author: G. Lopez
Author: A. McNeill
Author: C. Moorby
Author: H. Morris
Author: K.E. Morrison ORCID iD
Author: E. Mudanohwo
Author: S.S. O'Sullivan
Author: J. Pearson
Author: R. Pearson
Author: J.S. Perlmutter
Author: H. Petursson
Author: M. Pirinen
Author: B. Post
Author: S. Potter
Author: B. Ravina
Author: T. Revesz
Author: O. Riess
Author: F. Rivadeneira
Author: P. Rizzu
Author: M. Ryten
Author: S. Sawcer
Author: A. Schapira
Author: H. Scheffer
Author: K. Shaw
Author: I. Shoulson
Author: E. Sidransky
Author: R. de Silva
Author: C. Smith
Author: C.C. Spencer
Author: H. Stefansson
Author: S. Steinberg
Author: J.D. Stockton
Author: A. Strange
Author: Z. Su
Author: K. Talbot
Author: C.M. Tanner
Author: A. Tashakkori-Ghanbaria
Author: D. Trabzuni
Author: B.J. Traynor
Author: G. Uitterlinden
Author: J. Vandrovcova
Author: D. Velseboer
Author: D. Vukcevic
Author: R. Walker
Author: B. van de Warrenburg
Author: M.E. Weale
Author: M. Wickremaratchi
Author: N. Williams
Author: C.H. Williams-Gray
Author: S. Winder-Rhodes
Author: P. Donnelly
Author: N.W. Wood

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