Objective/Rationale:
A critical question which is still unresolved in the post GWAS (genome-wide association study) era focuses on the role of non genetic factors conferring either a risk or protective effect in PD. Interestingly, the PARK16 locus replicated by our GWAS contains interesting candidate genes which are thought to be target of environmental risk factors for PD. Therefore, it would be crucial to fine map and define the immediate biological consequences of all five risk loci identified by recent GWAS, to open up new avenues for PD research.
Project Description:
A total of 75 SNPs will be genotyped in approximately 20,000 cases and 20,000 controls. These SNPs were selected based on their p- values observed in our GWAS (cut off p<10-4). Effect estimates based on major vs. minor allele contrast will be computed. Results will be then synthesized across different sites using both fixed effect and random effect models. The fixed effect model assumes that the effect is the same in different populations. However, it does not take into account the heterogeneity, which usually exists in different populations. The random effect model takes into account this heterogeneity while assessing an association. One of the reason for lack of reproducibility in the association studies that most studies failed to incorporate heterogeneity in the study design and analysis.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The project is expected to produce important advancements for the diagnosis and treatment of patients. As novel disease genes and pathways are discovered, there will be more quantifiable read-outs that reflect disease susceptibility or progression (biomarkers), which may enter into clinical diagnosis or monitoring of drug treatment. Subsequent functional characterization of the identified targets integrates molecular genetics and cellular/animal models to define the molecular mechanisms of neurodegeneration and develop disease modulating therapies for the respective diseases.
Anticipated Outcome:
Our proposed study, apart from validating genetic effects, will for the first time delineate the role of non-genetic component from selected variants. Defining the role of genetic variants based on the involvement of non genetic factors will enable us to develop a set of risk panel which could be used in clinical practice to predict a risk to PD.
Final Outcome
Recently published meta- analysis of GWAS of Parkinson disease (PD) identified new potential genetic targets or ‘loci’, for PD, and thus increased the number of loci to be implicated in PD to eleven. Out of eleven loci, five are new. To assess the role of eleven loci in diverse populations, we performed a large scale world- wide replication study within the Genetic-Epidemiology of Parkinson disease (GEO-PD) consortium. A total of 21 sites representing 19 countries from 4 continents agreed to contribute DNA samples and clinical data for a total of 17705 individuals (8750 cases and 8950 controls). Our study confirms 9 of the 11postulated loci risk for PD. The confirmed loci include previously documented genes including SNCA, LRRK2, GAK, MAPT and BST1. Moreover, our study also confirmed the role of STK39, LAMP3, SYT11 and HIP1R loci and thus provided unequivocal support to the role of these loci for PD. Our results did not confirm the role of ACMSD gene in PD. Our results are in agreement with recently published GWAS. Our finding suggests that large-scale replication with direct genotyping is useful even for SNPs that pass conventional genome-wide significance thresholds.
Presentations & Publications
1. Manu SharmaCA, 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, 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 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 Krügeron on behalf of the GEOPD consortium. Worldwide replication and heterogeneity in Parkinson disease genetic loci. Under review Neurology (Corresponding author)
2. Large scale replication of GWAS of Parkinson disease, North Shore Systems, University of Chicago, 19th September 2011, Evanston, USA