Large-scale assessment of polyglutamine repeat expansions in Parkinson disease

Lisa Wang, Jan O. Aasly, Grazia Annesi, Soraya Bardien, Maria Bozi, Alexis Brice, Jonathan Carr, Sun J. Chung, Carl Clarke, David Crosiers, Angela Deutschländer, Gertrud Eckstein, Matthew J. Farrer, Stefano Goldwurm, Gaetan Garraux, Georgios M. Hadjigeorgiou, Andrew A. Hicks, Nobutaka Hattori, Christine Klein, Beom Jeon, Yun J. Kim, Suzanne Lesage, Juei-Jueng Lin, Timothy Lynch, Peter Lichtner, Anthony E. Lang, Vincent Mok, Barbara Jasinska-Myga, George D. Mellick, Karen E. Morrison, Grzegorz Opala, Lasse Pihlstrøm, Peter P. Pramstaller, Sung S. Park, Aldo Quattrone, Ekaterina Rogaeva, Owen A. Ross, Leonidas Stefanis, Joanne D. Stockton, Peter A. Silburn, Jessie Theuns, Eng K. Tan, Hiroyuki Tomiyama, Mathias Toft, Christine Van Broeckhoven, Ryan J. Uitti, Karin Wirdefeldt, Zbigniew Wszolek, Georgia Xiromerisiou, Kuo-Chu Yueh, Yi Zhao, Thomas Gasser, Demetrius M. Maraganore, Rejko Krüger, Manu Sharma, R.S Boyle, A Sellbach, J.D. O’Sullivan, G.T. Sutherland, G.A Siebert, N.N.W Dissanayaka, Christine Van Broeckhoven, Jessie Theuns, David Crosiers, Barbara Pickut, Sebastiaan Engelborghs, Bram Meeus, Peter P. De Deyn, Patrick Cras, Ekaterina Rogaeva, Anthony E Lang, Christophe Tzourio, Philippe Amouyel, Marie-Anne Loriot, Eugénie Mutez, Aurélie Duflot, Jean-Philippe Legendre, Nawal Waucquier, Thomas Gasser, Olaf Riess, Daniela Berg, Claudia Schulte, Christine Klein, Ana Djarmati, Johann Hagenah, Katja Lohman, Georg Auburger, Rüdiger Hilker, Simone van de Loo, Efthimios Dardiotis, Vaia Tsimourtou, Styliani Ralli, Persa Kountra, Gianna Patramani, Cristina Vogiatzi, Nobutaka Hattori, Hiroyuki Tomiyama, Manabu Funayama, Hiroyo Yoshino, Yuanzhe Li, Yoko Imamichi, Tatsushi Toda, Wataru Satake, Tim Lynch, Enza Maria Valente, Alessandro Ferraris, Bruno Dallapiccola, Tamara Ialongo, Laura Brighina, Barbara Corradi, Carlo Ferrarese, Monza Roberto Piolti, Patrizia Tarantino, Ferdinanda Annesi, Monica Gagliardi, Patrizia Tarantino, Beom S. Jeon, Sung-Sup Park, J Aasly, Grzegorz Opala, Barbara Jasinska-Myga, Gabriela Klodowska-Duda, Magdalena Boczarska-Jedynak, Eng King Tan, Andrea Carmine Belin, Lars Olson, Dagmar Galter, Marie Westerlund, Olaf Sydow, Christer Nilsson, Andreas Puschmann, JJ Lin, Demetrius M. Maraganore, J. Eric Ahlskog, Mariza de Andrade, Timothy G. Lesnick, Walter A. Rocca, Harvey Checkoway, Owen A Ross, Zbigniew K. Wszolek, Ryan J. Uitti

We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD). We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes. Fixed- and random-effects models were used to estimate the summary risk estimates for the genes. We investigated between-study heterogeneity and heterogeneity between different ethnic populations. We did not observe any definite pathogenic repeat expansions for SCA2, SCA3, SCA6, and SCA17 genes in patients with idiopathic PD from Caucasian and Asian populations. Furthermore, overall analysis did not reveal any significant association between intermediate repeats and PD. The effect estimates (odds ratio) ranged from 0.93 to 1.01 in the overall cohort for the SCA2, SCA3, SCA6, and SCA17 loci. Our study did not support a major role for definite pathogenic repeat expansions in SCA2, SCA3, SCA6, and SCA17 genes for idiopathic PD. Thus, results of this large study do not support diagnostic screening of SCA2, SCA3, SCA6, and SCA17 gene repeats in the common idiopathic form of PD. Likewise, this largest multicentered study performed to date excludes the role of intermediate repeats of these genes as a risk factor for PD.