Objective/Rationale:
Trinucleotide repeat expansion is a gene mutation where the codons (the groups of DNA components that correspond to amino acids) exceed the maximum of a certain gene. Variability in the expansion of trinucleotide repeats has a remarkable influence on disease: the larger the expansion, the earlier the onset and more severe the disease course. The variability in repeats size can cause a wide spectrum of neurodegenerative diseases including parkinsonism. This led us to hypothesize that clinically different yet mechanistically overlapping late-onset neurodegenerative diseases (i.e. trinucleotide repeat disorders and Parkinson’s disease) also share common genetic risk factors that might influence/modulate the disease susceptibility.
Project Description:
Repeats from six genes will be genotyped in approximately 20,000 cases and 20,000 controls. Association between repeat length and Parkinson’s disease will be evaluated adjusting for age, gender and ethnicity.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Our proposed study will provide quantifiable read-outs that reflect disease susceptibility or progression, which may enter into clinical diagnosis or monitoring of drug treatment. Subsequent functional characterization of the identified targets can help better understand molecular mechanisms of neurodegeneration and develop disease-modulating therapies for the respective diseases.
Anticipated Outcome:
Our proposed study will delineate low-risk carrier individuals from high-risk carrier individuals. These subsets can improve the diagnostic success and future personalized therapeutic strategies in Parkinson’s.
Progress Report
To decipher the role of SCA2, 3, 16 and 17 genes in Parkinson’s disease, we performed a large multi-centered study within the Genetic-Epidemiology of Parkinson’s disease (GEO-PD) consortium. A total of 26 sites representing 19 countries from four continents agreed to contribute DNA samples and clinical data for a total of 23,840 individuals (14,287 cases and 9,553 controls). Currently, analysis is underway and preliminary results will be presented to the steering committee.
Presentations & Publications
- 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, 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 Krüger on on behalf of the GEOPD consortium. Large scale clinico-genetic analysis of VPS35 and Parkinson disease. Journal of Medical Genetics 2012;49:721-726
- Florian Mittag, Finja Beuchel, Mohammad Saad, Andreas Jahn, Claudia Schulte, Zoltan Bochdanovits, Javier-Simon Sanchez, Mike A Nalls, Maragux Keller, Dena Hernandez, Raphael Gibbs, Alexandra Durr, Alexis Brice, Peter Heutink, Maria Martinez, Nicholas Wood, John Hardy, Andrew B. Singleton, Andreas Zell, Thomas Gasser and Manu Sharma for the International Parkinson’s Disease Genomics Consortium (IPDGC) Use of Support Vector Machine for disease risk predictions: Concerns and opportunities Human Mutation 2012 Dec;33(12):1708-18
- Finja Buechel, Florian Mittag, Andreas Zell, Thomas Gasser and Manu Sharma* Integrative Pathway Based Approaches for Genome-Wide Association Studies: Identification of new pathways for Crohn disease, Rheumatoid arthritis and Type-1 diabetes. PLoS One (under review)
- Invited lecture: Expanding repeats in Parkinson disease: Moving beyond association, Seoul National Medical School, Seoul, Republic of Korea, 08-10-2012
- Manu Sharma, Rejko Krüger and Thomas Gasser. LRRK2: Understanding the role of common and rare variants in Parkinson disease. Movement Disorders 2012 Apr;27(4):475
- Manu Sharma, Rejko Krueger, Thomas Gasser. From Genome-wide association studies to next generation sequencing: Lessons from the past and planning for the future. JAMA Neurology (under review)