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

Michael A. Nalls; Vincent Plagnol; Dena G. Hernandez; Manu Sharma; Una-Marie Sheerin; Mohamad Saad; Javier Simon-Sanchez; Claudia Schulte; Suzanne Lesage; Sigurlaug Sveinbjornsdottir; Sampath Arepalli; Roger Barker; Yoav Ben-Shlomo; Henk W. Berendse; Daniela Berg; Kailash Bhatia; Rob M. A. de Bie; Alessandro Biffi; Bas Bloem; Zoltan Bochdanovits; Michael Bonin; Jose M. Bras; 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; Philippe Damier; Jean-Francois Dartigues; Panos Deloukas; Guenther Deuschl; David T. Dexter; Karin D. van Dijk; Allissa Dillman; Frank Durif; Alexandra Duerr; Sarah Edkins; Jonathan R. Evans; Thomas Foltynie; Jianjun Gao; Michelle Gardner; J. Raphael Gibbs; Alison Goate; Emma Gray; Rita Guerreiro; Omar Gustafsson; Clare Harris; 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; Palmi V. Jonsson; Jean-Charles Lambert; Cordelia Langford; Andrew Lees; Peter Lichtner; Patricia Limousin; Grisel Lopez; Delia Lorenz; Alisdair McNeill; Catriona Moorby; Matthew Moore; Huw R. Morris; Karen E. Morrison; Ese Mudanohwo; Sean S. O'Sullivan; Justin Pearson; Joel S. Perlmutter; Hjoervar Petursson; Pierre Pollak; Bart Post; Simon Potter; Bernard Ravina; Tamas Revesz; Olaf Riess; Fernando Rivadeneira; Patrizia Rizzu; Mina Ryten; Stephen Sawcer; Anthony Schapira; Hans Scheffer; Karen Shaw; Ira Shoulson; Ellen Sidransky; Colin Smith; Chris C. A. Spencer; Hreinn Stefansson; Joanna D. Stockton; Amy Strange; Kevin Talbot; Carlie M. Tanner; Avazeh Tashakkori-Ghanbaria; Francois Tison; Daniah Trabzuni; Bryan J. Traynor; Andre G. Uitterlinden; Daan Velseboer; Marie Vidailhet; Robert Walker; Bart van de Warrenburg; Mirdhu Wickremaratchi; Nigel Williams; Caroline H. Williams-Gray; Sophie Winder-Rhodes; Kari Stefansson; Maria Martinez; John Hardy; Peter Heutink; Alexis Brice; Thomas Gasser; Andrew B. Singleton; Nicholas W. Wood; A. Durr

doi:https://doi.org/10.1016/S0140-6736(10)62345-8

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

Michael A. Nalls, Vincent Plagnol, Dena G. Hernandez, Manu Sharma, Una-Marie Sheerin, Mohamad Saad, Javier Simon-Sanchez, Claudia Schulte, Suzanne Lesage, Sigurlaug Sveinbjornsdottir, Sampath Arepalli, Roger Barker, Yoav Ben-Shlomo, Henk W. Berendse, Daniela Berg, Kailash Bhatia, Rob M. A. de Bie, Alessandro Biffi, Bas Bloem, Zoltan BochdanovitsMichael Bonin, Jose M. Bras, 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, Philippe Damier, Jean-Francois Dartigues, Panos Deloukas, Guenther Deuschl, David T. Dexter, Karin D. van Dijk, Allissa Dillman, Frank Durif, Alexandra Duerr, Sarah Edkins, Jonathan R. Evans, Thomas Foltynie, Jianjun Gao, Michelle Gardner, J. Raphael Gibbs, Alison Goate, Emma Gray, Rita Guerreiro, Omar Gustafsson, Clare Harris, 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, Palmi V. Jonsson, Jean-Charles Lambert, Cordelia Langford, Andrew Lees, Peter Lichtner, Patricia Limousin, Grisel Lopez, Delia Lorenz, Alisdair McNeill, Catriona Moorby, Matthew Moore, Huw R. Morris, Karen E. Morrison, Ese Mudanohwo, Sean S. O'Sullivan, Justin Pearson, Joel S. Perlmutter, Hjoervar Petursson, Pierre Pollak, Bart Post, Simon Potter, Bernard Ravina, Tamas Revesz, Olaf Riess, Fernando Rivadeneira, Patrizia Rizzu, Mina Ryten, Stephen Sawcer, Anthony Schapira, Hans Scheffer, Karen Shaw, Ira Shoulson, Ellen Sidransky, Colin Smith, Chris C. A. Spencer, Hreinn Stefansson, Joanna D. Stockton, Amy Strange, Kevin Talbot, Carlie M. Tanner, Avazeh Tashakkori-Ghanbaria, Francois Tison, Daniah Trabzuni, Bryan J. Traynor, Andre G. Uitterlinden, Daan Velseboer, Marie Vidailhet, Robert Walker, Bart van de Warrenburg, Mirdhu Wickremaratchi, Nigel Williams, Caroline H. Williams-Gray, Sophie Winder-Rhodes, Kari Stefansson, Maria Martinez, John Hardy, Peter Heutink, Alexis Brice, Thomas Gasser, Andrew B. Singleton, Nicholas W. Wood, A. Durr

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

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Abstract

Background Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. Methods We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated. Findings The discovery phase consisted of 5333 case and 12 019 control samples, with genotyped and imputed data at 7 689 524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p <5x10(-8)). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BSTI, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60.3% (95% CI 43.7-69-3). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2.51 (95% CI 2.23-2.83) compared with 1.00 in the lowest quintile of disease risk. Interpretation These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies

Original language	English
Pages (from-to)	641-649
Journal	Lancet
Volume	377
Issue number	9766
DOIs	https://doi.org/10.1016/S0140-6736(10)62345-8
Publication status	Published - 2011

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https://doi.org/10.1016/S0140-6736(10)62345-8

Cite this

Nalls, M. A., Plagnol, V., Hernandez, D. G., Sharma, M., Sheerin, U.-M., Saad, M., Simon-Sanchez, J., Schulte, C., Lesage, S., Sveinbjornsdottir, S., Arepalli, S., Barker, R., Ben-Shlomo, Y., Berendse, H. W., Berg, D., Bhatia, K., de Bie, R. M. A., Biffi, A., Bloem, B., ... Durr, A. (2011). Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet, 377(9766), 641-649. https://doi.org/10.1016/S0140-6736(10)62345-8

@article{f0a5fead36ab473684f69a8f0c5bec99,

title = "Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies",

abstract = "Background Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. Methods We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated. Findings The discovery phase consisted of 5333 case and 12 019 control samples, with genotyped and imputed data at 7 689 524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p <5x10(-8)). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BSTI, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60.3% (95% CI 43.7-69-3). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2.51 (95% CI 2.23-2.83) compared with 1.00 in the lowest quintile of disease risk. Interpretation These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies",

author = "Nalls, {Michael A.} and Vincent Plagnol and Hernandez, {Dena G.} and Manu Sharma and Una-Marie Sheerin and Mohamad Saad and Javier Simon-Sanchez and Claudia Schulte and Suzanne Lesage and Sigurlaug Sveinbjornsdottir and Sampath Arepalli and Roger Barker 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 Bras, {Jose M.} 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 Philippe Damier and Jean-Francois Dartigues and Panos Deloukas and Guenther Deuschl and Dexter, {David T.} and {van Dijk}, {Karin D.} and Allissa Dillman and Frank Durif and Alexandra Duerr and Sarah Edkins and Evans, {Jonathan R.} and Thomas Foltynie and Jianjun Gao and Michelle Gardner and Gibbs, {J. Raphael} and Alison Goate and Emma Gray and Rita Guerreiro and Omar Gustafsson and Clare Harris 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 Jonsson, {Palmi V.} and Jean-Charles Lambert and Cordelia Langford and Andrew Lees and Peter Lichtner and Patricia Limousin and Grisel Lopez and Delia Lorenz and Alisdair McNeill and Catriona Moorby and Matthew Moore and Morris, {Huw R.} and Morrison, {Karen E.} and Ese Mudanohwo and O'Sullivan, {Sean S.} and Justin Pearson and Perlmutter, {Joel S.} and Hjoervar Petursson and Pierre Pollak and Bart Post and Simon Potter 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 Colin Smith and Spencer, {Chris C. A.} and Hreinn Stefansson and Stockton, {Joanna D.} and Amy Strange and Kevin Talbot and Tanner, {Carlie M.} and Avazeh Tashakkori-Ghanbaria and Francois Tison and Daniah Trabzuni and Traynor, {Bryan J.} and Uitterlinden, {Andre G.} and Daan Velseboer and Marie Vidailhet and Robert Walker and {van de Warrenburg}, Bart and Mirdhu Wickremaratchi and Nigel Williams and Williams-Gray, {Caroline H.} and Sophie Winder-Rhodes and Kari Stefansson and Maria Martinez and John Hardy and Peter Heutink and Alexis Brice and Thomas Gasser and Singleton, {Andrew B.} and Wood, {Nicholas W.} and A. Durr",

year = "2011",

doi = "https://doi.org/10.1016/S0140-6736(10)62345-8",

language = "English",

volume = "377",

pages = "641--649",

journal = "Lancet",

issn = "0140-6736",

publisher = "Elsevier Limited",

number = "9766",

}

Nalls, MA, Plagnol, V, Hernandez, DG, Sharma, M, Sheerin, U-M, Saad, M, Simon-Sanchez, J, Schulte, C, Lesage, S, Sveinbjornsdottir, S, Arepalli, S, Barker, R, Ben-Shlomo, Y, Berendse, HW, Berg, D, Bhatia, K, de Bie, RMA, Biffi, A, Bloem, B, Bochdanovits, Z, Bonin, M, Bras, JM, Brockmann, K, Brooks, J, Burn, DJ, Charlesworth, G, Chen, H, Chinnery, PF, Chong, S, Clarke, CE, Cookson, MR, Cooper, JM, Corvol, JC, Counsell, C, Damier, P, Dartigues, J-F, Deloukas, P, Deuschl, G, Dexter, DT, van Dijk, KD, Dillman, A, Durif, F, Duerr, A, Edkins, S, Evans, JR, Foltynie, T, Gao, J, Gardner, M, Gibbs, JR, Goate, A, Gray, E, Guerreiro, R, Gustafsson, O, Harris, C, 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, Lambert, J-C, Langford, C, Lees, A, Lichtner, P, Limousin, P, Lopez, G, Lorenz, D, McNeill, A, Moorby, C, Moore, M, Morris, HR, Morrison, KE, Mudanohwo, E, O'Sullivan, SS, Pearson, J, Perlmutter, JS, Petursson, H, Pollak, P, 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, Smith, C, Spencer, CCA, Stefansson, H, Stockton, JD, Strange, A, Talbot, K, Tanner, CM, Tashakkori-Ghanbaria, A, Tison, F, Trabzuni, D, Traynor, BJ, Uitterlinden, AG, Velseboer, D, Vidailhet, M, Walker, R, van de Warrenburg, B, Wickremaratchi, M, Williams, N, Williams-Gray, CH, Winder-Rhodes, S, Stefansson, K, Martinez, M, Hardy, J, Heutink, P, Brice, A, Gasser, T, Singleton, AB, Wood, NW & Durr, A 2011, 'Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies', Lancet, vol. 377, no. 9766, pp. 641-649. https://doi.org/10.1016/S0140-6736(10)62345-8

TY - JOUR

T1 - Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies

AU - Nalls, Michael A.

AU - Plagnol, Vincent

AU - Hernandez, Dena G.

AU - Sharma, Manu

AU - Sheerin, Una-Marie

AU - Saad, Mohamad

AU - Simon-Sanchez, Javier

AU - Schulte, Claudia

AU - Lesage, Suzanne

AU - Sveinbjornsdottir, Sigurlaug

AU - Arepalli, Sampath

AU - Barker, Roger

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 - Bras, Jose M.

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 - Damier, Philippe

AU - Dartigues, Jean-Francois

AU - Deloukas, Panos

AU - Deuschl, Guenther

AU - Dexter, David T.

AU - van Dijk, Karin D.

AU - Dillman, Allissa

AU - Durif, Frank

AU - Duerr, Alexandra

AU - Edkins, Sarah

AU - Evans, Jonathan R.

AU - Foltynie, Thomas

AU - Gao, Jianjun

AU - Gardner, Michelle

AU - Gibbs, J. Raphael

AU - Goate, Alison

AU - Gray, Emma

AU - Guerreiro, Rita

AU - Gustafsson, Omar

AU - Harris, Clare

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 - Jonsson, Palmi V.

AU - Lambert, Jean-Charles

AU - Langford, Cordelia

AU - Lees, Andrew

AU - Lichtner, Peter

AU - Limousin, Patricia

AU - Lopez, Grisel

AU - Lorenz, Delia

AU - McNeill, Alisdair

AU - Moorby, Catriona

AU - Moore, Matthew

AU - Morris, Huw R.

AU - Morrison, Karen E.

AU - Mudanohwo, Ese

AU - O'Sullivan, Sean S.

AU - Pearson, Justin

AU - Perlmutter, Joel S.

AU - Petursson, Hjoervar

AU - Pollak, Pierre

AU - Post, Bart

AU - Potter, Simon

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 - Smith, Colin

AU - Spencer, Chris C. A.

AU - Stefansson, Hreinn

AU - Stockton, Joanna D.

AU - Strange, Amy

AU - Talbot, Kevin

AU - Tanner, Carlie M.

AU - Tashakkori-Ghanbaria, Avazeh

AU - Tison, Francois

AU - Trabzuni, Daniah

AU - Traynor, Bryan J.

AU - Uitterlinden, Andre G.

AU - Velseboer, Daan

AU - Vidailhet, Marie

AU - Walker, Robert

AU - van de Warrenburg, Bart

AU - Wickremaratchi, Mirdhu

AU - Williams, Nigel

AU - Williams-Gray, Caroline H.

AU - Winder-Rhodes, Sophie

AU - Stefansson, Kari

AU - Martinez, Maria

AU - Hardy, John

AU - Heutink, Peter

AU - Brice, Alexis

AU - Gasser, Thomas

AU - Singleton, Andrew B.

AU - Wood, Nicholas W.

AU - Durr, A.

PY - 2011

Y1 - 2011

N2 - Background Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. Methods We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated. Findings The discovery phase consisted of 5333 case and 12 019 control samples, with genotyped and imputed data at 7 689 524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p <5x10(-8)). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BSTI, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60.3% (95% CI 43.7-69-3). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2.51 (95% CI 2.23-2.83) compared with 1.00 in the lowest quintile of disease risk. Interpretation These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies

AB - Background Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. Methods We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated. Findings The discovery phase consisted of 5333 case and 12 019 control samples, with genotyped and imputed data at 7 689 524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p <5x10(-8)). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BSTI, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60.3% (95% CI 43.7-69-3). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2.51 (95% CI 2.23-2.83) compared with 1.00 in the lowest quintile of disease risk. Interpretation These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies

U2 - https://doi.org/10.1016/S0140-6736(10)62345-8

DO - https://doi.org/10.1016/S0140-6736(10)62345-8

M3 - Article

SN - 0140-6736

VL - 377

SP - 641

EP - 649

JO - Lancet

JF - Lancet

IS - 9766

ER -