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

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

doi:10.1136/jnnp-2012-304475

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

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

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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.

Original language	English
Pages (from-to)	666-673
Journal	Journal of neurology, neurosurgery, and psychiatry
Volume	84
Issue number	6
DOIs	https://doi.org/10.1136/jnnp-2012-304475
Publication status	Published - 07 May 2013
Externally published	Yes

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10.1136/jnnp-2012-304475Licence: CC BY-NC

The Val158Met COMT polymorphism
Copyright 2013 the authors. This is an open access Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/3.0/), which permits use, distribution and reproduction for non-commercial purposes, provided the author and source are cited.
Final published version, 199 KBLicence: CC BY-NC

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Klebe, S., Golmard, J.-L., Nalls, M. A., Saad, M., Singleton, A. B., Bras, J. M., Hardy, J., Simon-Sanchez, J., Heutink, P., Kuhlenbaumer, G., Charfi, R., Klein, C., Hagenah, J., Gasser, T., Wurster, I., Lesage, S., Lorenz, D., Deuschl, G., Durif, F., ... Wood, N. W. (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. https://doi.org/10.1136/jnnp-2012-304475

@article{2b35778c058040b197f4d99dc1cdac1d,

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.",

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

year = "2013",

month = may,

day = "7",

doi = "10.1136/jnnp-2012-304475",

language = "English",

volume = "84",

pages = "666--673",

journal = "Journal of neurology, neurosurgery, and psychiatry",

issn = "0022-3050",

publisher = "BMJ Publishing Group",

number = "6",

}

Klebe, S, Golmard, J-L, Nalls, MA, Saad, M, Singleton, AB, Bras, JM, Hardy, J, Simon-Sanchez, J, Heutink, P, Kuhlenbaumer, G, Charfi, R, Klein, C, Hagenah, J, Gasser, T, Wurster, I, Lesage, S, Lorenz, D, Deuschl, G, Durif, F, Pollak, P, Damier, P, Tison, F, Durr, A, Amouyel, P, Lambert, J-C, Tzourio, C, Maubaret, C, Charbonnier-Beaupel, F, Tahiri, K, Vidailhet, M, Martinez, M, Brice, A, Corvol, JC, Agid, Y, Anheim, M, Bonnet, A-M, Borg, M, Broussolle, E, Destee, A, Lohmann, E, Penet, C, Krack, P, Rascol, O, Tranchant, C, Verin, M, Viallet, F, Plagnol, V, Hernandez, DG, Sharma, M, Sheerin, U-M, Schulte, C, Sveinbjornsdottir, S, 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, Dartigues, J-F, Deloukas, P, Dexter, DT, van Dijk, KD, Dillman, A, Edkins, S, Evans, JR, Foltynie, T, Freeman, C, Gao, J, Gardner, M, Gibbs, R, Goate, A, Gray, E, Guerreiro, R, Gustafsson, 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, Jonsson, PV, Langford, C, Lees, A, Lichtner, P, Limousin, P, Lopez, G, McNeill, A, Moorby, C, Morris, H, Morrison, KE, Mudanohwo, E, O'Sullivan, SS, Pearson, J, Pearson, R, Perlmutter, JS, Petursson, H, Pirinen, M, 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, CCA, Stefansson, H, Steinberg, S, Stockton, JD, Strange, A, Su, Z, Talbot, K, Tanner, CM, Tashakkori-Ghanbaria, A, Trabzuni, D, Traynor, BJ, Uitterlinden, G, Vandrovcova, J, Velseboer, D, Vukcevic, D, Walker, R, van de Warrenburg, B, Weale, ME, Wickremaratchi, M, Williams, N, Williams-Gray, CH, Winder-Rhodes, S, Donnelly, P & Wood, NW 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, vol. 84, no. 6, pp. 666-673. https://doi.org/10.1136/jnnp-2012-304475

TY - JOUR

T1 - The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism

AU - Klebe, S.

AU - Golmard, J.-L.

AU - Nalls, M.A.

AU - Saad, Mohamad

AU - Singleton, A.B.

AU - Bras, J.M.

AU - Hardy, John

AU - Simon-Sanchez, J.

AU - Heutink, P.

AU - Kuhlenbaumer, G.

AU - Charfi, R.

AU - Klein, C.

AU - Hagenah, J.

AU - Gasser, T.

AU - Wurster, I.

AU - Lesage, S.

AU - Lorenz, D.

AU - Deuschl, G.

AU - Durif, F.

AU - Pollak, P.

AU - Damier, P.

AU - Tison, F.

AU - Durr, A.

AU - Amouyel, P.

AU - Lambert, Jean-Charles

AU - Tzourio, C.

AU - Maubaret, C.

AU - Charbonnier-Beaupel, F.

AU - Tahiri, K.

AU - Vidailhet, M.

AU - Martinez, Maria

AU - Brice, A.

AU - Corvol, J.C.

AU - Agid, Y.

AU - Anheim, M.

AU - Bonnet, A.-M.

AU - Borg, M.

AU - Broussolle, E.

AU - Destee, A.

AU - Lohmann, E.

AU - Penet, C.

AU - Krack, P.

AU - Rascol, O.

AU - Tranchant, C.

AU - Verin, M.

AU - Viallet, F.

AU - Plagnol, V.

AU - Hernandez, D.G.

AU - Sharma, Manu

AU - Sheerin, U.-M.

AU - Schulte, C.

AU - Sveinbjornsdottir, S.

AU - Arepalli, S.

AU - Band, G.

AU - Barker, Roger A

AU - Bellinguez, C.

AU - Ben-Shlomo, Y.

AU - Berendse, H.W.

AU - Berg, D.

AU - Bhatia, K.

AU - de Bie, R.M.

AU - Biffi, A.

AU - Bloem, B.

AU - Bochdanovits, Z.

AU - Bonin, M.

AU - Brockmann, K.

AU - Brooks, Janet

AU - Burn, D.J.

AU - Charlesworth, G.

AU - Chen, Honglei

AU - Chinnery, P.F.

AU - Chong, S.

AU - Clarke, Carl E.

AU - Cookson, M.R.

AU - Cooper, J. Mark

AU - Corvol, J.C.

AU - Counsell, C.

AU - Dartigues, J.-F.

AU - Deloukas, P.

AU - Dexter, D.T.

AU - van Dijk, K.D.

AU - Dillman, A.

AU - Edkins, S.

AU - Evans, J.R.

AU - Foltynie, T.

AU - Freeman, C.

AU - Gao, Jianjun

AU - Gardner, M.

AU - Gibbs, R.

AU - Goate, A.

AU - Gray, E.

AU - Guerreiro, R.

AU - Gustafsson, O.

AU - Harris, Clare

AU - Hellenthal, G.

AU - van Hilten, J.J.

AU - Hofman, A.

AU - Hollenbeck, A.

AU - Holton, J.

AU - Hu, Michele

AU - Huang, Xuemei

AU - Huber, H.

AU - Hudson, G.

AU - Hunt, S.E.

AU - Huttenlocher, J.

AU - Illig, T.

AU - Jonsson, P.V.

AU - Langford, C.

AU - Lees, Andrew

AU - Lichtner, P.

AU - Limousin, P.

AU - Lopez, G.

AU - McNeill, Alisdair

AU - Moorby, C.

AU - Morris, Huw

AU - Morrison, Karen E

AU - Mudanohwo, E.

AU - O'Sullivan, S.S.

AU - Pearson, J.

AU - Pearson, R.

AU - Perlmutter, J.S.

AU - Petursson, H.

AU - Pirinen, M.

AU - Post, B.

AU - Potter, S.

AU - Ravina, B.

AU - Revesz, T.

AU - Riess, O.

AU - Rivadeneira, F.

AU - Rizzu, P.

AU - Ryten, M.

AU - Sawcer, S.

AU - Schapira, A.

AU - Scheffer, H.

AU - Shaw, K.

AU - Shoulson, I.

AU - Sidransky, E.

AU - de Silva, R.

AU - Smith, Colin

AU - Spencer, Chris CA

AU - Stefansson, H.

AU - Steinberg, S.

AU - Stockton, J.D.

AU - Strange, A.

AU - Su, Zhan

AU - Talbot, K.

AU - Tanner, C.M.

AU - Tashakkori-Ghanbaria, A.

AU - Trabzuni, D.

AU - Traynor, B.J.

AU - Uitterlinden, G.

AU - Vandrovcova, J.

AU - Velseboer, D.

AU - Vukcevic, D.

AU - Walker, Robert

AU - van de Warrenburg, B.

AU - Weale, M.E.

AU - Wickremaratchi, M.

AU - Williams, N.

AU - Williams-Gray, C.H.

AU - Winder-Rhodes, S.

AU - Donnelly, Peter

AU - Wood, N.W.

PY - 2013/5/7

Y1 - 2013/5/7

N2 - 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.

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.

U2 - 10.1136/jnnp-2012-304475

DO - 10.1136/jnnp-2012-304475

M3 - Article

SN - 0022-3050

VL - 84

SP - 666

EP - 673

JO - Journal of neurology, neurosurgery, and psychiatry

JF - Journal of neurology, neurosurgery, and psychiatry

IS - 6

ER -

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

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