Portal de Periódicos da CAPES

Large-scale replication and heterogeneity in Parkinson disease genetic loci

2012; Lippincott Williams & Wilkins; Volume: 79; Issue: 7 Linguagem: Inglês

10.1212/wnl.0b013e318264e353

1526-632X

Manu Sharma, John P. A. Ioannidis, Jan Aasly, Grazia Annesi, Alexis Brice, Christine Van Broeckhoven, Lars Bertram, Maria Bozi, David Crosiers, Carl E Clarke, Maurizio Facheris, Matthew J. Farrer, Gaëtan Garraux, Suzana Gispert, Georg Auburger, Carles Vilariño‐Güell, Georgios M. Hadjigeorgiou, Andrew A. Hicks, Nobutaka Hattori, Beom S. Jeon, Suzanne Lesage, Christina M. Lill, Juei-Jueng Lin, Timothy Lynch, Peter Lichtner, Anthony E. Lang, Vincent Mok, Barbara Jasińska‐Myga, George D. Mellick, Karen Morrison, Grzegorz Opala, Peter P. Pramstaller, Irene Pichler, Sung Sup Park, Aldo Quattrone, Ekaterina Rogaeva, Owen A. Ross, Leonidas Stefanis, Joanne Stockton, Wataru Satake, Peter A. Silburn, Jessie Theuns, Eng-King Tan, Tatsushi Toda, Hiroyuki Tomiyama, Ryan J. Uitti, Karin Wirdefeldt, Zbigniew K. Wszołek, Georgia Xiromerisiou, Kuo-Chu Yueh, Yi Zhao, Thomas Gasser, Demetrius M. Maraganore, Rejko Krüger, R.S Boyle, A Sellbach, John D. O’Sullivan, Greg T. Sutherland, G. Siebert, N. Dissanayaka, Christine Van Broeckhoven, Jessie Theuns, David Crosiers, Barbara Pickut, Sebastiaan Engelborghs, Bram Meeus, Peter Paul De Deyn, Patrick Cras, Ekaterina Rogaeva, Anthony E. Lang, Y. Agid, Mathieu Anheim, A-M Bonnet, Michael Borg, Alexis Brice, E. Broussolle, Jean‐Christophe Corvol, Philippe Damier, A. Destée, Alexandra Dürr, F. Durif, Suzanne Lesage, Ebba Lohmann, Pierre Pollak, Olivier Rascol, François Tison, Christine Tranchant, François Viallet, Marie Vidailhet, 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 Lohmann, Georg Auburger, Rüdiger Hilker, Simone van de Loo, Efthimios Dardiotis, Vaïa 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, J. Mark Gibson, Enza Maria Valente, Alessandro Ferraris, Bruno Dallapiccola, Tàmara Ialongo, Laura Brighina, B. Corradi, Roberto Piolti, Patrizia Tarantino, Ferdinanda Annesi, Beom S. Jeon, Sung Sup Park, Jan Aasly, Grzegorz Opala, Barbara Jasińska‐Myga, Gabriela Kłodowska-Duda, Magdalena Boczarska‐Jedynak, Eng King Tan, Andrea Carmine Belin, Lar̀s Olson, Dagmar Galter, Marie Westerlund, Olof Sydow, Christer Nilsson, Andreas Puschmann, J-J Lin, Demetrius M. Maraganore, Eric Ahlskog J, Mariza de Andrade, Timothy G. Lesnick, Walter A. Rocca, Harvey Checkoway, Owen A. Ross, Zbigniew K. Wszołek, Ryan J. Uitti,

RNA regulation and disease

Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.