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

Stephan Klebe; Jean Louis Golmard; Michael A. Nalls; Mohamad Saad; Andrew B. Singleton; Jose M. Bras; John Hardy; Javier Simon-Sanchez; Peter Heutink; Gregor Kuhlenbäumer; Rim Charfi; Christine Klein; Johann Hagenah; Thomas Gasser; Isabel Wurster; Suzanne Lesage; Delia Lorenz; Günther Deuschl; Franck Durif; Pierre Pollak; Philippe Damier; François Tison; Alexandra Durr; Philippe Amouyel; Jean Charles Lambert; Christophe Tzourio; Cécilia Maubaret; Fanny Charbonnier-Beaupel; Khadija Tahiri; Marie Vidailhet; Maria Martinez; Alexis Brice; Jean Christophe Corvol; Y. Agid; M. Anheim; A. M. Bonnet; M. Borg; A. Brice; E. Broussolle; J. C. Corvol; Ph Damier; A. Destée; F. Durif; S. Klebe; E. Lohmann; M. Martinez; C. Penet; P. Pollak; P. Krack; O. Rascol; F. Tison; C. Tranchant; M. Vérin; F. Viallet; M. Vidailhet; Michael A. Nalls; Vincent Plagnol; Jose M. Bras; Dena G. Hernandez; Manu Sharma; Una Marie Sheerin; Claudia Schulte; Sigurlaug Sveinbjörnsdóttir; Sampath Arepalli; Gavin Band; Damjan Vukcevic; Roger A. Barker; Céline Bellinguez; Yoav Ben-Shlomo; Henk W. Berendse; Daniela Berg; Kailash Bhatia; Rob M.A. De Bie; Alessandro Biffi; Bas Bloem; Zoltan Bochdanovits; Michael Bonin; Kathrin Brockmann; Janet Brooks; David J. Burn; Gavin Charlesworth; Honglei Chen; Patrick F. Chinnery; Sean Chong; Carl E. Clarke; Mark R. Cookson; J. Mark Cooper; Jean Christophe Corvol; Carl Counsell; Jean François Dartigues; Panos Deloukas; David T. Dexter; Karin D. Van Dijk; Allissa Dillman; Frank Durif; Sarah Edkins; Jonathan R. Evans; Thomas Foltynie; Colin Freeman; Jianjun Gao; Michelle Gardner; Raphael Gibbs; Alison Goate; Emma Gray; Rita Guerreiro; Ómar Gústafsson; Clare Harris; Garrett Hellenthal; Jacobus J. Van Hilten; Albert Hofman; Albert Hollenbeck; Janice Holton; Michele Hu; Xuemei Huang; Heiko Huber; Gavin Hudson; Sarah E. Hunt; Johanna Huttenlocher; Thomas Illig; Pálmi V. Jónsson; Cordelia Langford; Andrew Lees; Peter Lichtner; Patricia Limousin; Grisel Lopez; Alisdair McNeill; Catriona Moorby; Matthew Moore; Huw Morris; Karen E. Morrison; Ese Mudanohwo; Sean S. O'Sullivan; Justin Pearson; Richard Pearson; Joel S. Perlmutter; Hjörvar Pétursson; Matti Pirinen; Bart Post; Bernard Ravina; Tamas Revesz; Olaf Riess; Fernando Rivadeneira; Patrizia Rizzu; Mina Ryten; Stephen Sawcer; Anthony Schapira; Hans Scheffer; Karen Shaw; Ira Shoulson; Ellen Sidransky; Rohan De Silva; Colin Smith; Chris C.A. Spencer; Hreinn Stefánsson; Stacy Steinberg; Joanna D. Stockton; Amy Strange; Zhan Su; Kevin Talbot; Carlie M. Tanner; Avazeh Tashakkori-Ghanbaria; Daniah Trabzuni; Bryan J. Traynor; André G. Uitterlinden; Jana Vandrovcova; Daan Velseboer; Vidailhet Marie Vidailhet; Robert Walker; Bart Van De Warrenburg; Michael E. Weale; Mirdhu Wickremaratchi; Nigel Williams; Caroline H. Williams-Gray; Sophie Winder-Rhodes; Kári Stefánsson; Nicholas W. Wood; Andrew B. Singleton

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

Stephan Klebe, Jean Louis Golmard, Michael A. Nalls, Mohamad Saad, Andrew B. Singleton, Jose M. Bras, John Hardy, Javier Simon-Sanchez, Peter Heutink, Gregor Kuhlenbäumer, Rim Charfi, Christine Klein, Johann Hagenah, Thomas Gasser, Isabel Wurster, Suzanne Lesage, Delia Lorenz, Günther Deuschl, Franck Durif, Pierre PollakPhilippe Damier, François Tison, Alexandra Durr, Philippe Amouyel, Jean Charles Lambert, Christophe Tzourio, Cécilia Maubaret, Fanny Charbonnier-Beaupel, Khadija Tahiri, Marie Vidailhet, Maria Martinez, Alexis Brice, Jean Christophe Corvol, Y. Agid, M. Anheim, A. M. Bonnet, M. Borg, A. Brice, E. Broussolle, J. C. Corvol, Ph Damier, A. Destée, F. Durif, S. Klebe, E. Lohmann, M. Martinez, C. Penet, P. Pollak, P. Krack, O. Rascol, F. Tison, C. Tranchant, M. Vérin, F. Viallet, M. Vidailhet, Michael A. Nalls, Vincent Plagnol, Jose M. Bras, Dena G. Hernandez, Manu Sharma, Una Marie Sheerin, Claudia Schulte, Sigurlaug Sveinbjörnsdóttir, Sampath Arepalli, Gavin Band, Damjan Vukcevic, Roger A. Barker, Céline Bellinguez, Yoav Ben-Shlomo, Henk W. Berendse, Daniela Berg, Kailash Bhatia, Rob M.A. De Bie, Alessandro Biffi, Bas Bloem, Zoltan Bochdanovits, Michael Bonin, Kathrin Brockmann, Janet Brooks, David J. Burn, Gavin Charlesworth, Honglei Chen, Patrick F. Chinnery, Sean Chong, Carl E. Clarke, Mark R. Cookson, J. Mark Cooper, Jean Christophe Corvol, Carl Counsell, Jean François Dartigues, Panos Deloukas, David T. Dexter, Karin D. Van Dijk, Allissa Dillman, Frank Durif, Sarah Edkins, Jonathan R. Evans, Thomas Foltynie, Colin Freeman, Jianjun Gao, Michelle Gardner, Raphael Gibbs, Alison Goate, Emma Gray, Rita Guerreiro, Ómar Gústafsson, Clare Harris, Garrett Hellenthal, Jacobus J. Van Hilten, Albert Hofman, Albert Hollenbeck, Janice Holton, Michele Hu, Xuemei Huang, Heiko Huber, Gavin Hudson, Sarah E. Hunt, Johanna Huttenlocher, Thomas Illig, Pálmi V. Jónsson, Cordelia Langford, Andrew Lees, Peter Lichtner, Patricia Limousin, Grisel Lopez, Alisdair McNeill, Catriona Moorby, Matthew Moore, Huw Morris, Karen E. Morrison, Ese Mudanohwo, Sean S. O'Sullivan, Justin Pearson, Richard Pearson, Joel S. Perlmutter, Hjörvar Pétursson, Matti Pirinen, Bart Post, Bernard Ravina, Tamas Revesz, Olaf Riess, Fernando Rivadeneira, Patrizia Rizzu, Mina Ryten, Stephen Sawcer, Anthony Schapira, Hans Scheffer, Karen Shaw, Ira Shoulson, Ellen Sidransky, Rohan De Silva, Colin Smith, Chris C.A. Spencer, Hreinn Stefánsson, Stacy Steinberg, Joanna D. Stockton, Amy Strange, Zhan Su, Kevin Talbot, Carlie M. Tanner, Avazeh Tashakkori-Ghanbaria, Daniah Trabzuni, Bryan J. Traynor, André G. Uitterlinden, Jana Vandrovcova, Daan Velseboer, Vidailhet Marie Vidailhet, Robert Walker, Bart Van De Warrenburg, Michael E. Weale, Mirdhu Wickremaratchi, Nigel Williams, Caroline H. Williams-Gray, Sophie Winder-Rhodes, Kári Stefánsson, Nicholas W. Wood, Andrew B. Singleton

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

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
Number of pages	8
Journal	Journal of Neurology, Neurosurgery and Psychiatry
Volume	84
Issue number	6
DOIs	https://doi.org/10.1136/jnnp-2012-304475
State	Published - Jun 1 2013

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10.1136/jnnp-2012-304475

Cite this

Klebe, S., Golmard, J. L., Nalls, M. A., Saad, M., Singleton, A. B., Bras, J. M., Hardy, J., Simon-Sanchez, J., Heutink, P., Kuhlenbäumer, G., Charfi, R., Klein, C., Hagenah, J., Gasser, T., Wurster, I., Lesage, S., Lorenz, D., Deuschl, G., Durif, F., ... Singleton, A. B. (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{b219f33cac9b49799441949b886becd8,

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 = "Stephan Klebe and Golmard, {Jean Louis} and Nalls, {Michael A.} and Mohamad Saad and Singleton, {Andrew B.} and Bras, {Jose M.} and John Hardy and Javier Simon-Sanchez and Peter Heutink and Gregor Kuhlenb{\"a}umer and Rim Charfi and Christine Klein and Johann Hagenah and Thomas Gasser and Isabel Wurster and Suzanne Lesage and Delia Lorenz and G{\"u}nther Deuschl and Franck Durif and Pierre Pollak and Philippe Damier and Fran{\c c}ois Tison and Alexandra Durr and Philippe Amouyel and Lambert, {Jean Charles} and Christophe Tzourio and C{\'e}cilia Maubaret and Fanny Charbonnier-Beaupel and Khadija Tahiri and Marie Vidailhet and Maria Martinez and Alexis Brice and Corvol, {Jean Christophe} and Y. Agid and M. Anheim and Bonnet, {A. M.} and M. Borg and A. Brice and E. Broussolle and Corvol, {J. C.} and Ph Damier and A. Dest{\'e}e and F. Durif and S. Klebe and E. Lohmann and M. Martinez and C. Penet and P. Pollak and P. Krack and O. Rascol and F. Tison and C. Tranchant and M. V{\'e}rin and F. Viallet and M. Vidailhet and Nalls, {Michael A.} and Vincent Plagnol and Bras, {Jose M.} and Hernandez, {Dena G.} and Manu Sharma and Sheerin, {Una Marie} and Claudia Schulte and Sigurlaug Sveinbj{\"o}rnsd{\'o}ttir and Sampath Arepalli and Gavin Band and Damjan Vukcevic and Barker, {Roger A.} and C{\'e}line Bellinguez and Yoav Ben-Shlomo and Berendse, {Henk W.} and Daniela Berg and Kailash Bhatia and {De Bie}, {Rob M.A.} and Alessandro Biffi and Bas Bloem and Zoltan Bochdanovits and Michael Bonin and Kathrin Brockmann and Janet Brooks and Burn, {David J.} and Gavin Charlesworth and Honglei Chen and Chinnery, {Patrick F.} and Sean Chong and Clarke, {Carl E.} and Cookson, {Mark R.} and Cooper, {J. Mark} and Corvol, {Jean Christophe} and Carl Counsell and Dartigues, {Jean Fran{\c c}ois} and Panos Deloukas and Dexter, {David T.} and {Van Dijk}, {Karin D.} and Allissa Dillman and Frank Durif and Sarah Edkins and Evans, {Jonathan R.} and Thomas Foltynie and Colin Freeman and Jianjun Gao and Michelle Gardner and Raphael Gibbs and Alison Goate and Emma Gray and Rita Guerreiro and {\'O}mar G{\'u}stafsson and Clare Harris and Garrett Hellenthal and {Van Hilten}, {Jacobus J.} and Albert Hofman and Albert Hollenbeck and Janice Holton and Michele Hu and Xuemei Huang and Heiko Huber and Gavin Hudson and Hunt, {Sarah E.} and Johanna Huttenlocher and Thomas Illig and J{\'o}nsson, {P{\'a}lmi V.} and Cordelia Langford and Andrew Lees and Peter Lichtner and Patricia Limousin and Grisel Lopez and Alisdair McNeill and Catriona Moorby and Matthew Moore and Huw Morris and Morrison, {Karen E.} and Ese Mudanohwo and O'Sullivan, {Sean S.} and Justin Pearson and Richard Pearson and Perlmutter, {Joel S.} and Hj{\"o}rvar P{\'e}tursson and Matti Pirinen and Bart Post and Bernard Ravina and Tamas Revesz and Olaf Riess and Fernando Rivadeneira and Patrizia Rizzu and Mina Ryten and Stephen Sawcer and Anthony Schapira and Hans Scheffer and Karen Shaw and Ira Shoulson and Ellen Sidransky and {De Silva}, Rohan and Colin Smith and Spencer, {Chris C.A.} and Hreinn Stef{\'a}nsson and Stacy Steinberg and Stockton, {Joanna D.} and Amy Strange and Zhan Su and Kevin Talbot and Tanner, {Carlie M.} and Avazeh Tashakkori-Ghanbaria and Daniah Trabzuni and Traynor, {Bryan J.} and Uitterlinden, {Andr{\'e} G.} and Jana Vandrovcova and Daan Velseboer and {Marie Vidailhet}, Vidailhet and Robert Walker and {Van De Warrenburg}, Bart and Weale, {Michael E.} and Mirdhu Wickremaratchi and Nigel Williams and Williams-Gray, {Caroline H.} and Sophie Winder-Rhodes and K{\'a}ri Stef{\'a}nsson and Wood, {Nicholas W.} and Singleton, {Andrew B.}",

year = "2013",

month = jun,

day = "1",

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

language = "English",

volume = "84",

pages = "666--673",

journal = "Journal of Neurology, Neurosurgery and Psychiatry",

issn = "0022-3050",

number = "6",

}

Klebe, S, Golmard, JL, Nalls, MA, Saad, M, Singleton, AB, Bras, JM, Hardy, J, Simon-Sanchez, J, Heutink, P, Kuhlenbäumer, 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, JC, Tzourio, C, Maubaret, C, Charbonnier-Beaupel, F, Tahiri, K, Vidailhet, M, Martinez, M, Brice, A, Corvol, JC, Agid, Y, Anheim, M, Bonnet, AM, Borg, M, Brice, A, Broussolle, E, Corvol, JC, Damier, P, Destée, 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, Vidailhet, M, Nalls, MA, Plagnol, V, Bras, JM, Hernandez, DG, Sharma, M, Sheerin, UM, Schulte, C, Sveinbjörnsdóttir, S, Arepalli, S, Band, G, Vukcevic, D, Barker, RA, Bellinguez, C, Ben-Shlomo, Y, Berendse, HW, Berg, D, Bhatia, K, De Bie, RMA, 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, 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, Ó, 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, McNeill, A, Moorby, C, Moore, M, Morris, H, Morrison, KE, Mudanohwo, E, O'Sullivan, SS, Pearson, J, Pearson, R, Perlmutter, JS, Pétursson, H, Pirinen, M, Post, B, 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, Stefánsson, H, Steinberg, S, Stockton, JD, Strange, A, Su, Z, Talbot, K, Tanner, CM, Tashakkori-Ghanbaria, A, Trabzuni, D, Traynor, BJ, Uitterlinden, AG, Vandrovcova, J, Velseboer, D, Marie Vidailhet, V, Walker, R, Van De Warrenburg, B, Weale, ME, Wickremaratchi, M, Williams, N, Williams-Gray, CH, Winder-Rhodes, S, Stefánsson, K, Wood, NW & Singleton, AB 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, Stephan

AU - Golmard, Jean Louis

AU - Nalls, Michael A.

AU - Saad, Mohamad

AU - Singleton, Andrew B.

AU - Bras, Jose M.

AU - Hardy, John

AU - Simon-Sanchez, Javier

AU - Heutink, Peter

AU - Kuhlenbäumer, Gregor

AU - Charfi, Rim

AU - Klein, Christine

AU - Hagenah, Johann

AU - Gasser, Thomas

AU - Wurster, Isabel

AU - Lesage, Suzanne

AU - Lorenz, Delia

AU - Deuschl, Günther

AU - Durif, Franck

AU - Pollak, Pierre

AU - Damier, Philippe

AU - Tison, François

AU - Durr, Alexandra

AU - Amouyel, Philippe

AU - Lambert, Jean Charles

AU - Tzourio, Christophe

AU - Maubaret, Cécilia

AU - Charbonnier-Beaupel, Fanny

AU - Tahiri, Khadija

AU - Vidailhet, Marie

AU - Martinez, Maria

AU - Brice, Alexis

AU - Corvol, Jean Christophe

AU - Agid, Y.

AU - Anheim, M.

AU - Bonnet, A. M.

AU - Borg, M.

AU - Brice, A.

AU - Broussolle, E.

AU - Corvol, J. C.

AU - Damier, Ph

AU - Destée, A.

AU - Durif, F.

AU - Klebe, S.

AU - Lohmann, E.

AU - Martinez, M.

AU - Penet, C.

AU - Pollak, P.

AU - Krack, P.

AU - Rascol, O.

AU - Tison, F.

AU - Tranchant, C.

AU - Vérin, M.

AU - Viallet, F.

AU - Vidailhet, M.

AU - Nalls, Michael A.

AU - Plagnol, Vincent

AU - Bras, Jose M.

AU - Hernandez, Dena G.

AU - Sharma, Manu

AU - Sheerin, Una Marie

AU - Schulte, Claudia

AU - Sveinbjörnsdóttir, Sigurlaug

AU - Arepalli, Sampath

AU - Band, Gavin

AU - Vukcevic, Damjan

AU - Barker, Roger A.

AU - Bellinguez, Céline

AU - Ben-Shlomo, Yoav

AU - Berendse, Henk W.

AU - Berg, Daniela

AU - Bhatia, Kailash

AU - De Bie, Rob M.A.

AU - Biffi, Alessandro

AU - Bloem, Bas

AU - Bochdanovits, Zoltan

AU - Bonin, Michael

AU - Brockmann, Kathrin

AU - Brooks, Janet

AU - Burn, David J.

AU - Charlesworth, Gavin

AU - Chen, Honglei

AU - Chinnery, Patrick F.

AU - Chong, Sean

AU - Clarke, Carl E.

AU - Cookson, Mark R.

AU - Cooper, J. Mark

AU - Corvol, Jean Christophe

AU - Counsell, Carl

AU - Dartigues, Jean François

AU - Deloukas, Panos

AU - Dexter, David T.

AU - Van Dijk, Karin D.

AU - Dillman, Allissa

AU - Durif, Frank

AU - Edkins, Sarah

AU - Evans, Jonathan R.

AU - Foltynie, Thomas

AU - Freeman, Colin

AU - Gao, Jianjun

AU - Gardner, Michelle

AU - Gibbs, Raphael

AU - Goate, Alison

AU - Gray, Emma

AU - Guerreiro, Rita

AU - Gústafsson, Ómar

AU - Harris, Clare

AU - Hellenthal, Garrett

AU - Van Hilten, Jacobus J.

AU - Hofman, Albert

AU - Hollenbeck, Albert

AU - Holton, Janice

AU - Hu, Michele

AU - Huang, Xuemei

AU - Huber, Heiko

AU - Hudson, Gavin

AU - Hunt, Sarah E.

AU - Huttenlocher, Johanna

AU - Illig, Thomas

AU - Jónsson, Pálmi V.

AU - Langford, Cordelia

AU - Lees, Andrew

AU - Lichtner, Peter

AU - Limousin, Patricia

AU - Lopez, Grisel

AU - McNeill, Alisdair

AU - Moorby, Catriona

AU - Moore, Matthew

AU - Morris, Huw

AU - Morrison, Karen E.

AU - Mudanohwo, Ese

AU - O'Sullivan, Sean S.

AU - Pearson, Justin

AU - Pearson, Richard

AU - Perlmutter, Joel S.

AU - Pétursson, Hjörvar

AU - Pirinen, Matti

AU - Post, Bart

AU - Ravina, Bernard

AU - Revesz, Tamas

AU - Riess, Olaf

AU - Rivadeneira, Fernando

AU - Rizzu, Patrizia

AU - Ryten, Mina

AU - Sawcer, Stephen

AU - Schapira, Anthony

AU - Scheffer, Hans

AU - Shaw, Karen

AU - Shoulson, Ira

AU - Sidransky, Ellen

AU - De Silva, Rohan

AU - Smith, Colin

AU - Spencer, Chris C.A.

AU - Stefánsson, Hreinn

AU - Steinberg, Stacy

AU - Stockton, Joanna D.

AU - Strange, Amy

AU - Su, Zhan

AU - Talbot, Kevin

AU - Tanner, Carlie M.

AU - Tashakkori-Ghanbaria, Avazeh

AU - Trabzuni, Daniah

AU - Traynor, Bryan J.

AU - Uitterlinden, André G.

AU - Vandrovcova, Jana

AU - Velseboer, Daan

AU - Marie Vidailhet, Vidailhet

AU - Walker, Robert

AU - Van De Warrenburg, Bart

AU - Weale, Michael E.

AU - Wickremaratchi, Mirdhu

AU - Williams, Nigel

AU - Williams-Gray, Caroline H.

AU - Winder-Rhodes, Sophie

AU - Stefánsson, Kári

AU - Wood, Nicholas W.

AU - Singleton, Andrew B.

PY - 2013/6/1

Y1 - 2013/6/1

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.

UR - http://www.scopus.com/inward/record.url?scp=84877634080&partnerID=8YFLogxK

U2 - 10.1136/jnnp-2012-304475

DO - 10.1136/jnnp-2012-304475

M3 - Article

C2 - 23408064

AN - SCOPUS:84877634080

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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