Mutant genes linked to Parkinson's in some: study
Sun Nov 15, 1:20 pm ET
HONG KONG (Reuters) – People of Japanese and European descent who have mutant versions of five genes may be at higher risk of developing Parkinson's disease, two large teams of researchers have found.
The two independent studies, published in the latest issue of Nature Genetics, involved more than 25,000 participants in total and are the largest studies to date to try to uncover genetic associations behind Parkinson's disease.
A study in Japan looked only at ethnic Japanese while a second study, in the United States, focused only on people of European heritage.
In the first study, Tatsushi Toda of Japan's Kobe University and colleagues sequenced the genes of 2,011 participants with the disease and 18,381 others without the disease.
They found that those with the disease had variants of the genes PARK16, BST1, SNCA and LRRK2.
In the second study, researchers led by Andrew Singleton at the National Institutes of Health's (NIH) laboratory of neurogenetics in the United States analyzed the genes of more than 5,000 patients of European ancestry who suffer from the disease and detected strong links between Parkinson's and variants of the genes SNCA and MAPT.
The two teams later compared their data and found that variants of PARK16, SNCA and LRRK2 carry risk of Parkinson's in both Japanese and European populations, while variants of BST1 and MAPT were population-specific.
"Because previous Parkinson's genome-wide association studies were too small and lacked power, we worked together to compile and analyze the large data sets needed to identify the elusive genetic variations that play a role in this complex disease," Singleton said in a statement.
"With this better understanding of the underlying genetic variants involved in the progress of this disorder, we have more insight into the causes and underlying biology of this disease.
"We hope this new understanding will one day provide us with strategies to delay, or even prevent, the development of Parkinson's disease."
Parkinson's is a neurodegenerative disease that affects one to two percent of people over the age of 65. It is characterized by tremors, sluggish movement, muscle stiffness, and difficulty with balance.
Although medical treatments may improve symptoms, there are none that can slow down or halt the progression of the disease.
(Reporting by Tan Ee Lyn; editing by Michael Roddy)
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Related abstracts from Nature Genetics...
Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease
Wataru Satake1,2,3, Yuko Nakabayashi1,2, Ikuko Mizuta1,2, Yushi Hirota1,2, Chiyomi Ito1,2, Michiaki Kubo4, Takahisa Kawaguchi4, Tatsuhiko Tsunoda4, Masahiko Watanabe5, Atsushi Takeda6, Hiroyuki Tomiyama7, Kenji Nakashima8, Kazuko Hasegawa9, Fumiya Obata10, Takeo Yoshikawa11, Hideshi Kawakami12, Saburo Sakoda3, Mitsutoshi Yamamoto13, Nobutaka Hattori7, Miho Murata14, Yusuke Nakamura4,15 & Tatsushi Toda1,2
To identify susceptibility variants for Parkinson's disease (PD), we performed a genome-wide association study (GWAS) and two replication studies in a total of 2,011 cases and 18,381 controls from Japan. We identified a new susceptibility locus on 1q32 (P = 1.52 times 10-12) and designated this as PARK16, and we also identified BST1 on 4p15 as a second new risk locus (P = 3.94 times 10-9). We also detected strong associations at SNCA on 4q22 (P = 7.35 times 10-17) and LRRK2 on 12q12 (P = 2.72 times 10-8), both of which are implicated in autosomal dominant forms of parkinsonism. By comparing results of a GWAS performed on individuals of European ancestry, we identified PARK16, SNCA and LRRK2 as shared risk loci for PD and BST1 and MAPT as loci showing population differences. Our results identify two new PD susceptibility loci, show involvement of autosomal dominant parkinsonism loci in typical PD and suggest that population differences contribute to genetic heterogeneity in PD.
1. Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan.
2. Division of Clinical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
3. Department of Neurology, Osaka University Graduate School of Medicine, Suita, Japan.
4. Center for Genomic Medicine, RIKEN, Yokohama, Japan.
5. Department of Neurology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
6. Division of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.
7. Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
8. Department of Neurology, Tottori University Faculty of Medicine, Yonago, Japan.
9. Department of Neurology, Sagamihara National Hospital, Sagamihara, Japan.
10. Division of Clinical Immunology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan.
11. RIKEN Brain Science Institute, Saitama, Japan.
12. Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
13. Department of Neurology, Kagawa Prefectural Central Hospital, Takamatsu, Japan.
14. Department of Neurology, National Center Hospital of Neurology and Psychiatry, Kodaira, Japan.
15. Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Correspondence to: Tatsushi Toda1,2 e-mail: toda@med.kobe-u.ac.jp
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Genome-wide association study reveals genetic risk underlying Parkinson's disease
Javier Simón-Sánchez1,2,22, Claudia Schulte3,22, Jose M Bras1,4,22, Manu Sharma3,22, J Raphael Gibbs1,5, Daniela Berg3, Coro Paisan-Ruiz5, Peter Lichtner6, Sonja W Scholz1,5, Dena G Hernandez1,5, Rejko Krüger3, Monica Federoff1, Christine Klein7, Alison Goate8, Joel Perlmutter8, Michael Bonin9, Michael A Nalls1, Thomas Illig10, Christian Gieger10, Henry Houlden5, Michael Steffens11, Michael S Okun12, Brad A Racette8, Mark R Cookson1, Kelly D Foote12, Hubert H Fernandez12, Bryan J Traynor1, Stefan Schreiber13, Sampath Arepalli1, Ryan Zonozi1, Katrina Gwinn14, Marcel van der Brug1,15, Grisel Lopez16, Stephen J Chanock17, Arthur Schatzkin17, Yikyung Park17, Albert Hollenbeck18, Jianjun Gao19, Xuemei Huang20, Nick W Wood5, Delia Lorenz21, Günther Deuschl21, Honglei Chen19, Olaf Riess9, John A Hardy5, Andrew B Singleton1 & Thomas Gasser3
We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding alpha-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 times 10-16) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 times 10-16). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS1, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 times 10-8) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 times 10-5). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.
1. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
2. Department of Clinical Genetics Section of Medical Genomics VU Medical Center De Boelelaan Amsterdam, The Netherlands.
3. Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases, Tübingen, Germany.
4. Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal.
5. Department of Molecular Neuroscience and Reta Lila Weston Laboratories, UCL Institute of Neurology, London, UK.
6. Institute of Human Genetics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
7. Section of Clinical and Molecular Neurogenetics at the Department of Neurology, University of Luebeck, Germany.
8. Department of Psychiatry and Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
9. Department of Medical Genetics, Institute of Human Genetics, University of Tübingen, Tübingen, Germany.
10. Institute of Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
11. Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
12. Movement Disorders Center, University of Florida, Gainesville, Florida, USA.
13. Institut für Klinische Molekularbiologie, Christian-Albrechts-Universität Kiel, Germany.
14. Department of Molecular and Human Genetics, Baylor College of Medicine, Texas, USA.
15. Department of Neuroscience, The Scripps Research Institute, Scripps, Florida, USA.
16. Parkinson's disease clinic, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
17. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
18. AARP, Washington, DC, USA.
19. Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, North Carolina, USA.
20. Departments of Neurology, Radiology, Neurosurgery, Pharmacology, Kinesiology and Bioengineering, Pennsylvania State University-Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA.
21. Klinik für Neurologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Christian-Albrechts-Universität Kiel, Kiel, Germany.
22. These authors contributed equally to this work.
Correspondence to: Thomas Gasser3 e-mail: thomas.gasser@uni-tuebingen.de
Correspondence to: Andrew B Singleton1 e-mail: singleta@mail.nih.gov
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