Large-scale replication and heterogeneity in Parkinson disease genetic loci

Manu Sharma, John P.A. Ioannidis, Jan O. Aasly, Grazia Annesi, Alexis Brice, Christine Van Broeckhoven, Lars Bertram, Maria Bozi, David Crosiers, Carl Clarke, Maurizio Facheris, Matthew Farrer, Gaetan Garraux, Suzana Gispert, Georg Auburger, Carles Vilariño-Güell, Georgios M. Hadjigeorgiou, Andrew A. Hicks, Nobutaka Hattori, Beom JeonSuzanne Lesage, Christina M. Lill, Juei Jueng Lin, Timothy Lynch, Peter Lichtner, Anthony E. Lang, Vincent Mok, Barbara Jasinska-Myga, George D. Mellick, Karen E. Morrison, Grzegorz Opala, Peter P. Pramstaller, Irene Pichler, Sung Sup Park, Aldo Quattrone, Ekaterina Rogaeva, Owen A. Ross, Leonidas Stefanis, Joanne D. Stockton, Wataru Satake, Peter A. Silburn, Jessie Theuns, Eng King Tan, Tatsushi Toda, Hiroyuki Tomiyama, Ryan J. Uitti, Karin Wirdefeldt, Zbigniew Wszolek, Georgia Xiromerisiou, Kuo Chu Yueh, Yi Zhao, Thomas Gasser, Demetrius Maraganore, Rejko Krüger

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

Objective: 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. Methods: 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. Results: 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 (I2 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)659-667
Number of pages9
JournalNeurology
Volume79
Issue number7
DOIs
StatePublished - Aug 14 2012

ASJC Scopus subject areas

  • Clinical Neurology

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