Genetic risk and age in Parkinson's disease: Continuum not stratum

被引：57

作者：

Nalls, Mike A. ^{[1
]}

Escott-Price, Valentina ^{[2
]}

Williams, Nigel M. ^{[2
]}

Lubbe, Steven ^{[3
]}

Keller, Margaux F. ^{[4
]}

Morris, Huw R. ^{[3
]}

Singleton, Andrew B. ^{[1
]}

机构：

[1] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA

[2] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales

[3] UCL Inst Neurol, Dept Clin Neurosci, London, England

[4] Merck Res Labs, Cambridge, MA USA

来源：

MOVEMENT DISORDERS | 2015年 / 30卷 / 06期

基金：

英国医学研究理事会;

关键词：

Parkinson's disease; genetics; age at onset; statistics; METAANALYSIS;

D O I：

10.1002/mds.26192

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

BackgroundRecent genomewide association study meta-analyses have identified 28 loci associated with risk of Parkinson's disease (PD). We sought to investigate whether these genetic risk factors are associated with PD age at onset. MethodsGenetic risk scores from these loci were calculated for 6,249 cases. Linear regression tested associations between cumulative genetic risk and PD age at onset. ResultsIncreasing genetic risk scores were associated with earlier age at onset (beta=-0.10, P=2.92 x 10(-8), adjusted r(2)=0.27). Single standard deviation increase in genetic risk score is associated with 37.44 d earlier age at onset. Highest genetic risk was found at 31 to 60 y, onset slightly below average age at onset (AAO). ConclusionsCommon genetic risk factors have a small but consistent association with AAO in PD. (c) 2015 International Parkinson and Movement Disorder Society

引用

页码：850 / 854

页数：5

共 10 条

[1] A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis [J].

Chio, Adriano ;

Schymick, Jennifer C. ;

Restagno, Gabriella ;

Scholz, Sonja W. ;

Lombardo, Federica ;

Lai, Shiao-Lin ;

Mora, Gabriele ;

Fung, Hon-Chung ;

Britton, Angela ;

Arepalli, Sampath ;

Gibbs, J. Raphael ;

Nalls, Michael ;

Berger, Stephen ;

Kwee, Lydia Coulter ;

Oddone, Eugene Z. ;

Ding, Jinhui ;

Crews, Cynthia ;

Rafferty, Ian ;

Washecka, Nicole ;

Hernandez, Dena ;

Ferrucci, Luigi ;

Bandinelli, Stefania ;

Guralnik, Jack ;

Macciardi, Fabio ;

Torri, Federica ;

Lupoli, Sara ;

Chanock, Stephen J. ;

Thomas, Gilles ;

Hunter, David J. ;

Gieger, Christian ;

Wichmann, H. Erich ;

Calvo, Andrea ;

Mutani, Roberto ;

Battistini, Stefania ;

Giannini, Fabio ;

Caponnetto, Claudia ;

Mancardi, Giovanni Luigi ;

La Bella, Vincenzo ;

Valentino, Francesca ;

Monsurro, Maria Rosaria ;

Tedeschi, Gioacchino ;

Marinou, Kalliopi ;

Sabatelli, Mario ;

Conte, Amelia ;

Mandrioli, Jessica ;

Sola, Patrizia ;

Salvi, Fabrizio ;

Bartolomei, Ilaria ;

Siciliano, Gabriele ;

Carlesi, Cecilia .

HUMAN MOLECULAR GENETICS, 2009, 18 (08) :1524-1532

[2] Genome Wide Assessment of Young Onset Parkinson's Disease from Finland [J].

Hernandez, Dena G. ;

Nalls, Michael A. ;

Ylikotila, Pauli ;

Keller, Margaux ;

Hardy, John A. ;

Majamaa, Kari ;

Singleton, Andrew B. .

PLOS ONE, 2012, 7 (07)

[3] Systematic Review and UK-Based Study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease [J].

Kilarski, Laura L. ;

Pearson, Justin P. ;

Newsway, Victoria ;

Majounie, Elisa ;

Knipe, M. Duleeka W. ;

Misbahuddin, Anjum ;

Chinnery, Patrick F. ;

Burn, David J. ;

Clarke, Carl E. ;

Marion, Marie-Helene ;

Lewthwaite, Alistair J. ;

Nicholl, David J. ;

Wood, Nicholas W. ;

Morrison, Karen E. ;

Williams-Gray, Caroline H. ;

Evans, Jonathan R. ;

Sawcer, Stephen J. ;

Barker, Roger A. ;

Wickremaratchi, Mirdhu M. ;

Ben-Shlomo, Yoav ;

Williams, Nigel M. ;

Morris, Huw R. .

MOVEMENT DISORDERS, 2012, 27 (12) :1522-1529

[4] Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database [J].

Lill, Christina M. ;

Roehr, Johannes T. ;

McQueen, Matthew B. ;

Kavvoura, Fotini K. ;

Bagade, Sachin ;

Schjeide, Brit-Maren M. ;

Schjeide, Leif M. ;

Meissner, Esther ;

Zauft, Ute ;

Allen, Nicole C. ;

Liu, Tian ;

Schilling, Marcel ;

Anderson, Kari J. ;

Beecham, Gary ;

Berg, Daniela ;

Biernacka, Joanna M. ;

Brice, Alexis ;

DeStefano, Anita L. ;

Do, Chuong B. ;

Eriksson, Nicholas ;

Factor, Stewart A. ;

Farrer, Matthew J. ;

Foroud, Tatiana ;

Gasser, Thomas ;

Hamza, Taye ;

Hardy, John A. ;

Heutink, Peter ;

Hill-Burns, Erin M. ;

Klein, Christine ;

Latourelle, Jeanne C. ;

Maraganore, Demetrius M. ;

Martin, Eden R. ;

Martinez, Maria ;

Myers, Richard H. ;

Nalls, Michael A. ;

Pankratz, Nathan ;

Payami, Haydeh ;

Satake, Wataru ;

Scott, William K. ;

Sharma, Manu ;

Singleton, Andrew B. ;

Stefansson, Kari ;

Toda, Tatsushi ;

Tung, Joyce Y. ;

Vance, Jeffery ;

Wood, Nick W. ;

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Massano, Joao ;

Bhatia, Kailash P. .

COLD SPRING HARBOR PERSPECTIVES IN MEDICINE, 2012, 2 (06)

[6] Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies [J].

Nalls, Michael A. ;

Plagnol, Vincent ;

Hernandez, Dena G. ;

Sharma, Manu ;

Sheerin, Una-Marie ;

Saad, Mohamad ;

Simon-Sanchez, Javier ;

Schulte, Claudia ;

Lesage, Suzanne ;

Sveinbjornsdottir, Sigurlaug ;

Arepalli, Sampath ;

Barker, Roger ;

Ben-Shlomo, Yoav ;

Berendse, Henk W. ;

Berg, Daniela ;

Bhatia, Kailash ;

de Bie, Rob M. A. ;

Biffi, Alessandro ;

Bloem, Bas ;

Bochdanovits, Zoltan ;

Bonin, Michael ;

Bras, Jose M. ;

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 ;

Damier, Philippe ;

Dartigues, Jean-Francois ;

Deloukas, Panos ;

Deuschl, Guenther ;

Dexter, David T. ;

van Dijk, Karin D. ;

Dillman, Allissa ;

Durif, Frank ;

Duerr, Alexandra ;

Edkins, Sarah ;

Evans, Jonathan R. ;

Foltynie, Thomas ;

Gao, Jianjun ;

Gardner, Michelle ;

Gibbs, J. Raphael ;

Goate, Alison .

LANCET, 2011, 377 (9766) :641-649

[7] Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease [J].

Nalls, Mike A. ;

Pankratz, Nathan ;

Lill, Christina M. ;

Do, Chuong B. ;

Hernandez, Dena G. ;

Saad, Mohamad ;

DeStefano, Anita L. ;

Kara, Eleanna ;

Bras, Jose ;

Sharma, Manu ;

Schulte, Claudia ;

Keller, Margaux F. ;

Arepalli, Sampath ;

Letson, Christopher ;

Edsall, Connor ;

Stefansson, Hreinn ;

Liu, Xinmin ;

Pliner, Hannah ;

Lee, Joseph H. ;

Cheng, Rong ;

Ikram, M. Arfan ;

Ioannidis, John P. A. ;

Hadjigeorgiou, Georgios M. ;

Bis, Joshua C. ;

Martinez, Maria ;

Perlmutter, Joel S. ;

Goate, Alison ;

Marder, Karen ;

Fiske, Brian ;

Sutherland, Margaret ;

Xiromerisiou, Georgia ;

Myers, Richard H. ;

Clark, Lorraine N. ;

Stefansson, Kari ;

Hardy, John A. ;

Heutink, Peter ;

Chen, Honglei ;

Wood, Nicholas W. ;

Houlden, Henry ;

Payami, Haydeh ;

Brice, Alexis ;

Scott, William K. ;

Gasser, Thomas ;

Bertram, Lars ;

Eriksson, Nicholas ;

Foroud, Tatiana ;

Singleton, Andrew B. .

NATURE GENETICS, 2014, 46 (09) :989-+

[8] A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses [J].

Ripatti, Samuli ;

Tikkanen, Emmi ;

Orho-Melander, Marju ;

Havulinna, Aki S. ;

Silander, Kaisa ;

Sharma, Amitabh ;

Guiducci, Candace ;

Perola, Markus ;

Jula, Antti ;

Sinisalo, Juha ;

Lokki, Marja-Liisa ;

Nieminen, Markku S. ;

Melander, Olle ;

Salomaa, Veikko ;

Peltonen, Leena ;

Kathiresan, Sekar .

LANCET, 2010, 376 (9750) :1393-1400

[9] Genome-wide association study reveals genetic risk underlying Parkinson's disease [J].

Simon-Sanchez, Javier ;

Schulte, Claudia ;

Bras, Jose M. ;

Sharma, Manu ;

Gibbs, J. Raphael ;

Berg, Daniela ;

Paisan-Ruiz, Coro ;

Lichtner, Peter ;

Scholz, Sonja W. ;

Hernandez, Dena G. ;

Krueger, Rejko ;

Federoff, Monica ;

Klein, Christine ;

Goate, Alison ;

Perlmutter, Joel ;

Bonin, Michael ;

Nalls, Michael A. ;

Illig, Thomas ;

Gieger, Christian ;

Houlden, Henry ;

Steffens, Michael ;

Okun, Michael S. ;

Racette, Brad A. ;

Cookson, Mark R. ;

Foote, Kelly D. ;

Fernandez, Hubert H. ;

Traynor, Bryan J. ;

Schreiber, Stefan ;

Arepalli, Sampath ;

Zonozi, Ryan ;

Gwinn, Katrina ;

van der Brug, Marcel ;

Lopez, Grisel ;

Chanock, Stephen J. ;

Schatzkin, Arthur ;

Park, Yikyung ;

Hollenbeck, Albert ;

Gao, Jianjun ;

Huang, Xuemei ;

Wood, Nick W. ;

Lorenz, Delia ;

Deuschl, Guenther ;

Chen, Honglei ;

Riess, Olaf ;

Hardy, John A. ;

Singleton, Andrew B. ;

Gasser, Thomas .

NATURE GENETICS, 2009, 41 (12) :1308-U68

[10] The Motor Phenotype of Parkinson's Disease in Relation to Age at Onset [J].

Wickremaratchi, Mirdhu M. ;

Knipe, M. Duleeka W. ;

Sastry, B. S. Dwarakanath ;

Morgan, Elizabeth ;

Jones, Anne ;

Salmon, Rachel ;

Weiser, Richard ;

Moran, Maralyn ;

Davies, Debbie ;

Ebenezer, Louise ;

Raha, Sandip ;

Robertson, Neil P. ;

Butler, Christopher C. ;

Ben-Shlomo, Yoav ;

Morris, Huw R. .

MOVEMENT DISORDERS, 2011, 26 (03) :457-463

← 1 →

共 10 条

[1] A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis [J].

Chio, Adriano ;

Schymick, Jennifer C. ;

Restagno, Gabriella ;

Scholz, Sonja W. ;

Lombardo, Federica ;

Lai, Shiao-Lin ;

Mora, Gabriele ;

Fung, Hon-Chung ;

Britton, Angela ;

Arepalli, Sampath ;

Gibbs, J. Raphael ;

Nalls, Michael ;

Berger, Stephen ;

Kwee, Lydia Coulter ;

Oddone, Eugene Z. ;

Ding, Jinhui ;

Crews, Cynthia ;

Rafferty, Ian ;

Washecka, Nicole ;

Hernandez, Dena ;

Ferrucci, Luigi ;

Bandinelli, Stefania ;

Guralnik, Jack ;

Macciardi, Fabio ;

Torri, Federica ;

Lupoli, Sara ;

Chanock, Stephen J. ;

Thomas, Gilles ;

Hunter, David J. ;

Gieger, Christian ;

Wichmann, H. Erich ;

Calvo, Andrea ;

Mutani, Roberto ;

Battistini, Stefania ;

Giannini, Fabio ;

Caponnetto, Claudia ;

Mancardi, Giovanni Luigi ;

La Bella, Vincenzo ;

Valentino, Francesca ;

Monsurro, Maria Rosaria ;

Tedeschi, Gioacchino ;

Marinou, Kalliopi ;

Sabatelli, Mario ;

Conte, Amelia ;

Mandrioli, Jessica ;

Sola, Patrizia ;

Salvi, Fabrizio ;

Bartolomei, Ilaria ;

Siciliano, Gabriele ;

Carlesi, Cecilia .

HUMAN MOLECULAR GENETICS, 2009, 18 (08) :1524-1532

[2] Genome Wide Assessment of Young Onset Parkinson's Disease from Finland [J].

Hernandez, Dena G. ;

Nalls, Michael A. ;

Ylikotila, Pauli ;

Keller, Margaux ;

Hardy, John A. ;

Majamaa, Kari ;

Singleton, Andrew B. .

PLOS ONE, 2012, 7 (07)

[3] Systematic Review and UK-Based Study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease [J].

Kilarski, Laura L. ;

Pearson, Justin P. ;

Newsway, Victoria ;

Majounie, Elisa ;

Knipe, M. Duleeka W. ;

Misbahuddin, Anjum ;

Chinnery, Patrick F. ;

Burn, David J. ;

Clarke, Carl E. ;

Marion, Marie-Helene ;

Lewthwaite, Alistair J. ;

Nicholl, David J. ;

Wood, Nicholas W. ;

Morrison, Karen E. ;

Williams-Gray, Caroline H. ;

Evans, Jonathan R. ;

Sawcer, Stephen J. ;

Barker, Roger A. ;

Wickremaratchi, Mirdhu M. ;

Ben-Shlomo, Yoav ;

Williams, Nigel M. ;

Morris, Huw R. .

MOVEMENT DISORDERS, 2012, 27 (12) :1522-1529

[4] Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database [J].

Lill, Christina M. ;

Roehr, Johannes T. ;

McQueen, Matthew B. ;

Kavvoura, Fotini K. ;

Bagade, Sachin ;

Schjeide, Brit-Maren M. ;

Schjeide, Leif M. ;

Meissner, Esther ;

Zauft, Ute ;

Allen, Nicole C. ;

Liu, Tian ;

Schilling, Marcel ;

Anderson, Kari J. ;

Beecham, Gary ;

Berg, Daniela ;

Biernacka, Joanna M. ;

Brice, Alexis ;

DeStefano, Anita L. ;

Do, Chuong B. ;

Eriksson, Nicholas ;

Factor, Stewart A. ;

Farrer, Matthew J. ;

Foroud, Tatiana ;

Gasser, Thomas ;

Hamza, Taye ;

Hardy, John A. ;

Heutink, Peter ;

Hill-Burns, Erin M. ;

Klein, Christine ;

Latourelle, Jeanne C. ;

Maraganore, Demetrius M. ;

Martin, Eden R. ;

Martinez, Maria ;

Myers, Richard H. ;

Nalls, Michael A. ;

Pankratz, Nathan ;

Payami, Haydeh ;

Satake, Wataru ;

Scott, William K. ;

Sharma, Manu ;

Singleton, Andrew B. ;

Stefansson, Kari ;

Toda, Tatsushi ;

Tung, Joyce Y. ;

Vance, Jeffery ;

Wood, Nick W. ;

Zabetian, Cyrus P. ;

Young, Peter ;

Tanzi, Rudolph E. ;

Khoury, Muin J. .

PLOS GENETICS, 2012, 8 (03)

[5] Clinical Approach to Parkinson's Disease: Features, Diagnosis, and Principles of Management [J].

Massano, Joao ;

Bhatia, Kailash P. .

COLD SPRING HARBOR PERSPECTIVES IN MEDICINE, 2012, 2 (06)

[6] Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies [J].

Nalls, Michael A. ;

Plagnol, Vincent ;

Hernandez, Dena G. ;

Sharma, Manu ;

Sheerin, Una-Marie ;

Saad, Mohamad ;

Simon-Sanchez, Javier ;

Schulte, Claudia ;

Lesage, Suzanne ;

Sveinbjornsdottir, Sigurlaug ;

Arepalli, Sampath ;

Barker, Roger ;

Ben-Shlomo, Yoav ;

Berendse, Henk W. ;

Berg, Daniela ;

Bhatia, Kailash ;

de Bie, Rob M. A. ;

Biffi, Alessandro ;

Bloem, Bas ;

Bochdanovits, Zoltan ;

Bonin, Michael ;

Bras, Jose M. ;

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 ;

Damier, Philippe ;

Dartigues, Jean-Francois ;

Deloukas, Panos ;

Deuschl, Guenther ;

Dexter, David T. ;

van Dijk, Karin D. ;

Dillman, Allissa ;

Durif, Frank ;

Duerr, Alexandra ;

Edkins, Sarah ;

Evans, Jonathan R. ;

Foltynie, Thomas ;

Gao, Jianjun ;

Gardner, Michelle ;

Gibbs, J. Raphael ;

Goate, Alison .

LANCET, 2011, 377 (9766) :641-649

[7] Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease [J].

Nalls, Mike A. ;

Pankratz, Nathan ;

Lill, Christina M. ;

Do, Chuong B. ;

Hernandez, Dena G. ;

Saad, Mohamad ;

DeStefano, Anita L. ;

Kara, Eleanna ;

Bras, Jose ;

Sharma, Manu ;

Schulte, Claudia ;

Keller, Margaux F. ;

Arepalli, Sampath ;

Letson, Christopher ;

Edsall, Connor ;

Stefansson, Hreinn ;

Liu, Xinmin ;

Pliner, Hannah ;

Lee, Joseph H. ;

Cheng, Rong ;

Ikram, M. Arfan ;

Ioannidis, John P. A. ;

Hadjigeorgiou, Georgios M. ;

Bis, Joshua C. ;

Martinez, Maria ;

Perlmutter, Joel S. ;

Goate, Alison ;

Marder, Karen ;

Fiske, Brian ;

Sutherland, Margaret ;

Xiromerisiou, Georgia ;

Myers, Richard H. ;

Clark, Lorraine N. ;

Stefansson, Kari ;

Hardy, John A. ;

Heutink, Peter ;

Chen, Honglei ;

Wood, Nicholas W. ;

Houlden, Henry ;

Payami, Haydeh ;

Brice, Alexis ;

Scott, William K. ;

Gasser, Thomas ;

Bertram, Lars ;

Eriksson, Nicholas ;

Foroud, Tatiana ;

Singleton, Andrew B. .

NATURE GENETICS, 2014, 46 (09) :989-+

[8] A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses [J].

Ripatti, Samuli ;

Tikkanen, Emmi ;

Orho-Melander, Marju ;

Havulinna, Aki S. ;

Silander, Kaisa ;

Sharma, Amitabh ;

Guiducci, Candace ;

Perola, Markus ;

Jula, Antti ;

Sinisalo, Juha ;

Lokki, Marja-Liisa ;

Nieminen, Markku S. ;

Melander, Olle ;

Salomaa, Veikko ;

Peltonen, Leena ;

Kathiresan, Sekar .

LANCET, 2010, 376 (9750) :1393-1400

[9] Genome-wide association study reveals genetic risk underlying Parkinson's disease [J].

Simon-Sanchez, Javier ;

Schulte, Claudia ;

Bras, Jose M. ;

Sharma, Manu ;

Gibbs, J. Raphael ;

Berg, Daniela ;

Paisan-Ruiz, Coro ;

Lichtner, Peter ;

Scholz, Sonja W. ;

Hernandez, Dena G. ;

Krueger, Rejko ;

Federoff, Monica ;

Klein, Christine ;

Goate, Alison ;

Perlmutter, Joel ;

Bonin, Michael ;

Nalls, Michael A. ;

Illig, Thomas ;

Gieger, Christian ;

Houlden, Henry ;

Steffens, Michael ;

Okun, Michael S. ;

Racette, Brad A. ;

Cookson, Mark R. ;

Foote, Kelly D. ;

Fernandez, Hubert H. ;

Traynor, Bryan J. ;

Schreiber, Stefan ;

Arepalli, Sampath ;

Zonozi, Ryan ;

Gwinn, Katrina ;

van der Brug, Marcel ;

Lopez, Grisel ;

Chanock, Stephen J. ;

Schatzkin, Arthur ;

Park, Yikyung ;

Hollenbeck, Albert ;

Gao, Jianjun ;

Huang, Xuemei ;

Wood, Nick W. ;

Lorenz, Delia ;

Deuschl, Guenther ;

Chen, Honglei ;

Riess, Olaf ;

Hardy, John A. ;

Singleton, Andrew B. ;

Gasser, Thomas .

NATURE GENETICS, 2009, 41 (12) :1308-U68

[10] The Motor Phenotype of Parkinson's Disease in Relation to Age at Onset [J].

Wickremaratchi, Mirdhu M. ;

Knipe, M. Duleeka W. ;

Sastry, B. S. Dwarakanath ;

Morgan, Elizabeth ;

Jones, Anne ;

Salmon, Rachel ;

Weiser, Richard ;

Moran, Maralyn ;

Davies, Debbie ;

Ebenezer, Louise ;

Raha, Sandip ;

Robertson, Neil P. ;

Butler, Christopher C. ;

Ben-Shlomo, Yoav ;

Morris, Huw R. .

MOVEMENT DISORDERS, 2011, 26 (03) :457-463

← 1 →