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 | |
| State | Published - Jun 1 2013 |
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The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism. / Klebe, Stephan; Golmard, Jean Louis; Nalls, Michael A.; Saad, Mohamad; Singleton, Andrew B.; Bras, Jose M.; Hardy, John; Simon-Sanchez, Javier; Heutink, Peter; Kuhlenbäumer, Gregor; Charfi, Rim; Klein, Christine; Hagenah, Johann; Gasser, Thomas; Wurster, Isabel; Lesage, Suzanne; Lorenz, Delia; Deuschl, Günther; Durif, Franck; Pollak, Pierre; Damier, Philippe; Tison, François; Durr, Alexandra; Amouyel, Philippe; Lambert, Jean Charles; Tzourio, Christophe; Maubaret, Cécilia; Charbonnier-Beaupel, Fanny; Tahiri, Khadija; Vidailhet, Marie; Martinez, Maria; Brice, Alexis; Corvol, Jean Christophe; Agid, Y.; Anheim, M.; Bonnet, A. M.; Borg, M.; Brice, A.; Broussolle, E.; Corvol, J. C.; Damier, Ph; 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, Michael A.; Plagnol, Vincent; Bras, Jose M.; Hernandez, Dena G.; Sharma, Manu; Sheerin, Una Marie; Schulte, Claudia; Sveinbjörnsdóttir, Sigurlaug; Arepalli, Sampath; Band, Gavin; Vukcevic, Damjan; Barker, Roger A.; Bellinguez, Céline; Ben-Shlomo, Yoav; Berendse, Henk W.; Berg, Daniela; Bhatia, Kailash; De Bie, Rob M.A.; Biffi, Alessandro; Bloem, Bas; Bochdanovits, Zoltan; Bonin, Michael; Brockmann, Kathrin; Brooks, Janet; Burn, David J.; Charlesworth, Gavin; Chen, Honglei; Chinnery, Patrick F.; Chong, Sean; Clarke, Carl E.; Cookson, Mark R.; Cooper, J. Mark; Corvol, Jean Christophe; Counsell, Carl; Dartigues, Jean François; Deloukas, Panos; Dexter, David T.; Van Dijk, Karin D.; Dillman, Allissa; Durif, Frank; Edkins, Sarah; Evans, Jonathan R.; Foltynie, Thomas; Freeman, Colin; Gao, Jianjun; Gardner, Michelle; Gibbs, Raphael; Goate, Alison; Gray, Emma; Guerreiro, Rita; Gústafsson, Ómar; Harris, Clare; Hellenthal, Garrett; Van Hilten, Jacobus J.; Hofman, Albert; Hollenbeck, Albert; Holton, Janice; Hu, Michele; Huang, Xuemei; Huber, Heiko; Hudson, Gavin; Hunt, Sarah E.; Huttenlocher, Johanna; Illig, Thomas; Jónsson, Pálmi V.; Langford, Cordelia; Lees, Andrew; Lichtner, Peter; Limousin, Patricia; Lopez, Grisel; McNeill, Alisdair; Moorby, Catriona; Moore, Matthew; Morris, Huw; Morrison, Karen E.; Mudanohwo, Ese; O'Sullivan, Sean S.; Pearson, Justin; Pearson, Richard; Perlmutter, Joel S.; Pétursson, Hjörvar; Pirinen, Matti; Post, Bart; Ravina, Bernard; Revesz, Tamas; Riess, Olaf; Rivadeneira, Fernando; Rizzu, Patrizia; Ryten, Mina; Sawcer, Stephen; Schapira, Anthony; Scheffer, Hans; Shaw, Karen; Shoulson, Ira; Sidransky, Ellen; De Silva, Rohan; Smith, Colin; Spencer, Chris C.A.; Stefánsson, Hreinn; Steinberg, Stacy; Stockton, Joanna D.; Strange, Amy; Su, Zhan; Talbot, Kevin; Tanner, Carlie M.; Tashakkori-Ghanbaria, Avazeh; Trabzuni, Daniah; Traynor, Bryan J.; Uitterlinden, André G.; Vandrovcova, Jana; Velseboer, Daan; Marie Vidailhet, Vidailhet; Walker, Robert; Van De Warrenburg, Bart; Weale, Michael E.; Wickremaratchi, Mirdhu; Williams, Nigel; Williams-Gray, Caroline H.; Winder-Rhodes, Sophie; Stefánsson, Kári; Wood, Nicholas W.; Singleton, Andrew B.
In: Journal of Neurology, Neurosurgery and Psychiatry, Vol. 84, No. 6, 01.06.2013, p. 666-673.Research output: Contribution to journal › Article › peer-review
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
VL - 84
SP - 666
EP - 673
JO - Journal of Neurology Neurosurgery and Psychiatry
JF - Journal of Neurology Neurosurgery and Psychiatry
SN - 0022-3050
IS - 6
ER -