A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease

V. Plagnol, M.A. Nalls, J.M. Bras, D.G. Hernandez, M. Sharma, U.M. Sheerin, M. Saad, J. Simon-Sanchez, C. Schulte, S. Lesage, S. Sveinbjornsdottir, P. Amouyel, S. Arepalli, G. Band, R.A. Barker, C. Bellinguez, Y. Ben-Shlomo, H.W. Berendse, D. Berg, K. BhatiaR.M.A. de Bie, A. Biffi, B. Bloem, Z. Bochdanovits, M. Bonin, K. Brockmann, J. Brooks, D.J. Burn, G. Charlesworth, H.L. Chen, P.F. Chinnery, S. Chong, C.E. Clarke, M.R. Cookson, J.M. Cooper, J.C. Corvol, C. Counsell, P. Damier, J.F. Dartigues, P. Deloukas, G. Deuschl, D.T. Dexter, K.D. van Dijk, A. Dillman, F. Durif, A. Durr, S. Edkins, J.R. Evans, T. Foltynie, C. Freeman, J.J. Gao, M. Gardner, J.R. Gibbs, A. Goate, E. Gray, R. Guerreiro, O. Gustafsson, C Harris, G. Hellenthal, J.J. van Hilten, A. Hofman, A. Hollenbeck, J. Holton, M. Hu, X.M. Huang, H. Huber, G. Hudson, S.E. Hunt, J. Huttenlocher, T. Illig, P.V. Jonsson, C. Langford, A. Lees, P. Lichtner, P. Limousin, G. Lopez, D. Lorenz, A. McNeill, C. Moorby, M. Moore, H. Morris, K.E. Morrison, E. Mudanohwo, S.S. O'Sullivan, J. Pearson, R. Pearson, J.S. Perlmutter, H. Petursson, M. Pirinen, P. Pollak, B. Post, S. Potter, B. Ravina, T. Revesz, O. Riess, F. Rivadeneira, P. Rizzu, M. Ryten, S. Sawcer, P. Heutink, N.W. Wood, Alexandra Duerr, Anthony Schapira, Hans Scheffer, Karen Shaw, Ira Shoulson, Ellen Sidransky, Rohan de Silva, Colin Smith, Chris C. A. Spencer, Hreinn Stefansson, Stacy Steinberg, Joanna D. Stockton, Amy Strange, Zhan Su, Kevin Talbot, Carlie M. Tanner, Avazeh Tashakkori-Ghanbaria, Francois Tison, Daniah Trabzuni, Bryan J. Traynor, Andre G. Uitterlinden, Jana Vandrovcova, Daan Velseboer, Marie Vidailhet, Damjan Vukcevic, Robert Walker, Bart van de Warrenburg, Michael E. Weale, Mirdhu Wickremaratchi, Nigel Williams, Caroline H. Williams-Gray, Sophie Winder-Rhodes, Kari Stefansson, Maria Martinez, Peter Donnelly, Andrew B. Singleton, John Hardy, Alexis Brice, Thomas Gasser

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Abstract

A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p <5x10(-10), PARK16/1q32, STX1B/16p11, FGF20/8p22, STBD1/4q21, and GPNMB/7p15). Two of these five loci have been suggested by previous association studies (PARK16/1q32, FGF20/8p22), and this study provides further support for these findings. Using a dataset of post-mortem brain samples assayed for gene expression (n = 399) and methylation (n = 292), we identified methylation and expression changes associated with PD risk variants in PARK16/1q32, GPNMB/7p15, and STX1B/16p11 loci, hence suggesting potential molecular mechanisms and candidate genes at these risk loci
Original languageEnglish
Article numbere1002142
Pages (from-to)e1002142
JournalPLOS Genetics
Volume7
Issue number6
DOIs
Publication statusPublished - 2011

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