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. 2012 Aug 14;79(7):659-67.
doi: 10.1212/WNL.0b013e318264e353. Epub 2012 Jul 11.

Large-scale replication and heterogeneity in Parkinson disease genetic loci

Manu Sharma  1 , 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 Jeon, Suzanne 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; GEO-PD Consortium
Collaborators, Affiliations

Large-scale replication and heterogeneity in Parkinson disease genetic loci

Manu Sharma et al. Neurology. .

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 (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.

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.

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Figures

Figure 1
Figure 1. Forest plot showing the comparison of effect of each single nucleotide polymorphism (SNP) in Caucasian and Asian population
Boxes indicate the summary effect estimate. SNPs in 3 loci (MAPT, SYT11, and ACMSD) were monomorphic in the Asian population and thus are not included in the graph. GAK SNP showed deviation from Hardy-Weinberg equilibrium in Asian series and thus excluded from the graph.
See this image and copyright information in PMC

Comment in

References

    1. Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature 2009; 461: 747– 753. - PMC - PubMed
    1. McCarthy MI, Abecasis GR, Cardon LR, et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev 2008; 9: 356– 369. - PubMed
    1. Simon-Sanchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 2009; 41: 1308– 1312. - PMC - PubMed
    1. Maraganore DM, de Andrade M, Lesnick TG, et al. High-resolution whole-genome association study of Parkinson disease. Am J Hum Genet 2005; 77: 685– 693. - PMC - PubMed
    1. Pankratz N, Wilk JB, Latourelle JC, et al. Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum Genet 2009; 124: 593– 605. - PMC - PubMed